Medical composition containing nitroetheneamine derivative or salt thereof as active constituent

ABSTRACT

A medical composition containing, as an active constituent, a nitroetheneamine derivative represented by the formula (I):                    
     wherein the substituents are as defined in the disclosure, its stereoisomers, its tautomers or a salt thereof.

This application is a 371 of PCT/JP99/05148 filed Sep. 21, 1999.

TECHNICAL FIELD

The present invention relates to a medical composition containing anitroetheneamine derivative or a salt thereof as an active constituent.

BACKGROUND ART

The present invention relates to a medical composition containing anitroetheneamine derivative or a salt thereof as an active constituent,which has excellent matrix metalloproteinase inhibitory activities andwhich is useful as an angiogenesis inhibitor, an anticancer agent, atumor cell infiltration inhibitor or a tumor metastasis inhibitor usefulfor treatment or prevention of cancer or inflammatory diseases, or as atherapeutic or preventive agent for an articular disease such as chronicarticular rheumatism, osteoarthritis or rheumatoid arthritis, or as atherapeutic or preventive agent for various diseases such as gingivitis,glomerular nephritis, interstitial nephritis, encephalomyelitis,arterial sclerosis, cirrhosis, restenosis, diabetic retinopathy,neovascular glaucoma, corneal ulcer, epidermolysis bullosa, herniateddisk, a bone resorption such as osteoporosis, multiple sclerosis,bronchial asthma, Alzheimer's disease or an autoimmune disorder (such asCrohn's disease or Sjögren's syndrome). Further, some of thenitroetheneamine derivatives and their salts which are activeconstituents of such medical compositions, are novel compounds, and thepresent invention relates also to such novel compounds.

Connective tissues of higher organisms are constituted by extracellularmatrices. Extracellular matrices maintain homeostatis of biodynamicfunctions by repeating new formation and degradation (reassembly)depending upon the functions or morphological features of the particulartissues. Matrix metalloproteinases (MMP) are primary enzymes involved inthe decomposition of extracellular matrices and characterized in thatthey have a bivalent zinc ion at the active center. Presence of about 20types of MMP has been confirmed up to now including a secreted-type anda membrane-anchored-type, and the physiological functions and in-vivodistributions of the respective molecules are being made clear. MMP in anormal living body acts at a site where restructuring of tissues isrequired, for example, at a fetal development or for wound healing.However, in order to prevent destruction of extracellular matrices morethan necessary, a strict regulation mechanism (regulation of expressionor feedback regulation) is functioning. Namely, MMP is usually secretedas an inactive substance by external stimulation and then converted toan active substance by various proteases. On the other hand, thedecomposition activities by MMP are controlled by TIMP (tissue inhibitorof metalloproteinase) as its endogenous inhibitor. However, if someabnormality occurs in the above control mechanism, and MMP becomesexcessive, various tissue diseases will be induced.

For example, {circle around (1)} with respect to MMP-9 (gelatinase B/92kDa type IV collagenase) having a strong decomposition activity againsttype IV collagen which is the main constituting component of a basementmembrane, no substantial expression is usually observed in human normaltissues. On the other hand, its over expression has been observed inmany epithelial cancer cells and hematopoletic cancer cells includingcells of breast cancer and lung cancer. {circle around (2)} In carcinomaof the colon and rectum, a positive correlation has been observedbetween the expression level of MMP-9 and the metastatic nature (M.Nakajima et al, Journal of National Cancer Institute, Vol. 82, 1890,(1990)). {circle around (3)} It has also been experimentally shown withrespect to various cancer cells that the metastatic potential orinfiltrating potential of cancer cells in which MMP-9 or MMP-2(gelatinase A/72 kDa type IV collagenase) is highly expressed, isadvanced as compared with cells in which such expression is low (D. R.Welch et al, Proceedings of the National Academy of Sciences of theUnited States of America, Vol. 87, 7687, (1990), S. Yamagata et al,Biochemical and Biophysical Research Communication, Vol. 151, 186-162(1988)). {circle around (4)} With respect to MMP-13 (collagenase 3), noexpression has been observed in normal cells, but its high expressionhas been observed in breast cancer cells (J. M. Freiji, M. Nakajima etal, Journal of Biological Chemistry, Vol. 269, 16766-76773, (1994)).

Thus, highly malignant metastatic cancer cells have abnormal motility,adhesion and tissue invasive potential in addition to abnormal growthnature inherent to neoplasm, and as one of the background factors,excess production of MMP is involved.

Further, it is already known that {circle around (1)} MMP is involved incapillary-like tube formation of cultured vascular endothelial cells (R.Montesano et al, Cell, Vol. 42, 469-477, (1985)), {circle around (2)}MMP acts as one of angiogenesis factors to promote tumor growth (T. Itohet al, Cancer Research, Vol. 58, 1048-1051, (1998)), or {circle around(3)} with melanoma cells wherein TIMP-2 is excessively expressed, thetissue-infiltration ability or the angiogenesis inducibility decreases(P. Valente et al, International Journal of Cancer, Vol. 75, 246-253(1998)).

On the other hand, if inflammatory cytokine is induced by some factor atthe joint region, and MMP-1 (interstitial collagenase) or MMP-3(Stromelysin 1) from synovial cells is excessively produced and storedin a large amount in the joint fluid, it acts on the joint cartilage todestroy the cartilage matrix, thus leading to so-called articulardiseases represented by symptoms such as pain, regulation of variablejoint region or deformations.

Further, it is known that in a coronary disease, MMP will promotemigration of smooth muscle cells from the vascular wall to the intimaand will promote formation of atherosclerotic plaques, and further thatit is involved in reconstruction after angioplasty in the anginaltherapy (D. C. Celentano et al, Journal of Clinical Pharmacology, Vol.37, 991-1000, (1997)).

Further, in gingivitis, an increase in the production of MMP-1(interstitial collagenase) is observed.

Thus, MMP is responsible for a wide range of physiological functions ina living body, and its overproduction will upset the homeostasis of theliving body and will induce a new disease or aggravation of pathology.Accordingly, a MMP inhibitor is considered to be useful as anangiogenesis inhibitor, an anticancer agent, a tumor cell infiltrationinhibitor or a tumor metastasis inhibitor, to be used for treatment orprevention of cancer or inflammatory diseases; a therapeutic orpreventive agent for an articular disease such as chronic articularrheumatism, osteoarthritis or rheumatoid arthritis; or as a therapeuticor preventive agent for various diseases such as gingivitis, glomerularnephritis, interstitial nephritis, encephalomyelitis, arterialsclerosis, cirrhosis, restenosis, diabetic retinopathy, neovascularglaucoma, corneal ulcer, epidermolysis bullosa, herniated disk, a boneresorption such as osteoporosis, multiple sclerosis, bronchial asthma,Alzheimer's disease or an autoimmune disorder (such as Crohn's diseaseor Sjögren's syndrome).

Heretofore, many compounds having MMP inhibition activities have beenreported (R. A. Nigel et al, Current Opinion on Therapeutic Patents,Vol. 4, 7-16, (1994), R. P. Beckett et al, Drug Discovery Today, Vol. 1,16-26, (1996)). However, most of them are peptide derivatives designedbased on the amino acid sequence of the enzymatic cleavage site in thecollagen molecule constituting the substrate of MMP, including, forexample, hydroxamic acid type compounds; thiol type compounds;carboxylic acid type compounds; phosphonate type compounds; andphosphinate type compounds. Among them, with respect to some compoundsincluding hydroxamic acid derivatives, clinical trial have been carriedout on diseases such as cancer and arthritis.

It is generally known that a MMP inhibitor having a peptide in the basicstructure has a low oral absorbance, and particularly, a hydroxamic acidtype MMP inhibitor is considered to be poor in the stability in plasma,and a carboxylic acid type MMP inhibitor is known to have high affinitywith plasma proteins and is hardly excreted. To overcome such problems,preparation of a new compound of non-peptide type has been attempted (A.Katrin et al, Journal of Medicinal Chemistry, Vol. 41, 2194-2200,(1998)). Recently, a MMP inhibitor containing, as an active constituent,a flavon or anthocyanisine as disclosed in JP-A-8-104628, or a condensedthiophene derivative type MMP inhibitor as disclosed in JP-A-10-130271,is known. However, it has not been known that a medical compositioncontaining, as an active constituent, a non-peptide typenitroetheneamine derivative or a salt thereof like the presentinvention, has a MMP inhibition activity, particularly a strong andselective enzyme inhibition activity against MMP-9 (gelatinase B/92 kDatype IV collagenase).

Some of the nitroetheneamine derivatives as active constituents ofmedical compositions of the present invention are known compounds asdisclosed in e.g. W090/5134, JP-A-2-171, JP-A-3-255072, JP-A-3-204848,East German Patent 107276, East German Patent 107674, JP-A-8-277253 andWO97/17954. These known compounds are usually employed mainly asinsecticides, but the compounds disclosed in WO97/17954 are employed aspainkillers. However, WO97/17954 discloses some of nitroetheneaminederivatives used in the present invention, merely by wording. It is notknown at all that the above-mentioned known compounds have MMPinhibition activities. Further, JP-B-58-404956 discloses compoundssimilar to nitroetheneamine derivatives used as active constituents inthe medical compositions of the present invention, as intermediates forcompounds useful as active constituents of medical compositions, butsuch compounds are distinguished from the nitroetheneamine derivativesin that they do not have leaving groups having a “N—N” structure.Further, in this publication, there is no such a disclosure that thesecompounds have MMP inhibition activities.

The present inventors have conducted an extensive study on the synthesisand the pharmacological activities of compounds having MMP inhibitionactivities, and as a result, have found nitroetheneamine derivatives orsalts thereof which are useful as active constituents of the medicalcompositions of the present invention, particularly as non-peptide typecompounds having strong and selective enzyme inhibition activitiesagainst MMP-9. Some of the nitroetheneamine derivatives or the saltsthereof are novel compounds, and such novel compounds, the process forproducing such novel compounds and the intermediates for the preparationof such novel compounds, are also included in the present invention.

DISCLOSURE OF THE INVENTION

Namely, the present invention relates to a medical compositioncontaining, as an active constituent, a nitroetheneamine derivativerepresented by the formula (I):

wherein

R¹ is a hydrogen atom, an alkyl group which may be substituted, analkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted or a cyano group;

each of R² and R³ which are independent of each other, is a hydrogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted or a —A—R⁷ group (wherein Ais S, SO, SO₂, SO₃, CO or CO₂, and R⁷ is a hydrogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted); or R² and R³ may form, together with the N atom, a N═CR⁸R⁹group (wherein each of R⁸ and R⁹ which are independent of each other, isa hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted, a cyano group, a nitrogroup, an alkoxy group which may be substituted, an alkylthio groupwhich may be substituted, an aryloxy group which may be substituted or a—A—R⁷ group (wherein A and R⁷ are as defined above));

each of R⁴ and R⁵ which are independent of each other, is a hydrogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted, an alkoxy group which maybe substituted, a —A—R⁷ group (wherein A and R⁷ are as defined above),an amino group which may be substituted, a cyano group, an ester group,a hydroxyl group or an aryloxy group which may be substituted; or R⁴ andR⁵ may form, together with the N atom, a N═CR⁸R⁹ group (wherein R⁸ andR⁹ are as defined above);

R⁶ is a hydrogen atom, a nitro group, a cyano group, a —A—R⁷ group(wherein A and R⁷ are as defined above), an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted, a heterocyclic group which may be substituted, an alkoxygroup which may be substituted, a halogen atom or an amino group whichmay be substituted; and further

at least two selected from R¹, R², R³, R⁴ and R⁵ may together form aring containing or not containing a hetero atom; or a salt thereof.

The salt of the nitroetheneamine derivative represented by the aboveformula (I) may be any pharmaceutically acceptable salt. For example, amineral acid salt such as a hydrochloride, a sulfate or a nitrate; anorganic acid salt such as a p-toluenesulfonate, a propanesulfonate or amethanesulfonate; an alkali metal salt such as a potassium salt or asodium salt; an alkaline earth metal salt such as a calcium salt; or anorganic amine salt such as a triethanolamine salt or atris(hydroxymethyl)aminomethane salt, may be mentioned. Further, amongthese salts, there may be ones having water of crystallization.

The alkyl moiety in the alkyl group which may be substituted, containedin R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, in the alkoxy group which maybe substituted, contained in R⁴, R⁵, R⁶, R⁸ and R⁹, or in the alkylthiogroup which may be substituted, contained in R⁸ and R⁹ in the aboveformula (I), may usually be one having a carbon number of from 1 to 18,such as a methyl group, an ethyl group, a propyl group, a butyl group, apentyl group, a hexyl group, an octyl group, a nonyl group, a decylgroup or a nonadecyl group, and they include structural isomers oflinear or branched aliphatic chains.

The alkenyl moiety of the alkenyl group which may be substituted,contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in the above formula(I), may be one having a carbon number of from 2 to 18, such as a vinylgroup, a propenyl group, a butenyl group, a pentenyl group, a hexenylgroup, a decenyl group or a nonadecenyl group, and they includestructural isomers of linear or branched aliphatic chains.

The alkynyl moiety of the alkynyl group which may be substituted,contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in the above formula(I), may be one having a carbon number of from 2 to 18, such as anethynyl group, a propynyl group, a butynyl group, a pentynyl group, ahexynyl group, a decynyl group or a nonadecynyl group, and they includestructural isomers of linear or branched aliphatic chains.

The cycloalkyl moiety of the cycloalkyl group which may be substituted,contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in the above formula(I), may be one having a carbon number of from 3 to 8, such as acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup or a cyclooctyl group.

The cycloalkenyl moiety of the cycloalkenyl group which may besubstituted, contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in theabove formula (I), may be one having a carbon number of from 5 to 8,such as a cyclopentenyl group, a cyclohexenyl group or a cyclooctenylgroup.

The aryl moiety in the aryl group which may be substituted, contained inR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, or in the aryloxy group which maybe substituted, contained in R⁴, R⁵, R⁸ and R⁹, in the above formula(I), may, for example, be a phenyl group, a naphthyl group, atetrahydronaphthyl group, an indanyl group, an adamanthyl group, anoradamanthyl group, a norbornanyl group or a norbornanonyl group.

The heterocyclic moiety in the heterocyclic group which may besubstituted, contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in theabove formula (I), may, for example, be a mononuclear heterocyclic groupsuch as a pyrrolyl group, pyrrolinyl group, a pyrrolidinyl group, afuranyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, athienyl group, a dihydrodithienyl group, a tetrahydrothienyl group, apyrazolyl group, a pyrazolinyl group, a pyrazolidinyl group, animidazolyl group, an imidazolinyl group, an imidazolidinyl group, anoxazolyl group, an oxazolinyl group, an oxazolidinyl group, anisoxazolyl group, an isoxazolinyl group, an isoxazolidinyl group, athiazolyl group, a thiazolinyl group, a thiazolidinyl group, anisothiazolyl group, an isothiazolinyl group, an isothiazolidinyl group,an oxadiazolyl group, an oxadiazolinyl group, an oxadiazolidinyl group,a thiadiazolyl group, a thiadiazolinyl group, a thiadiazolidinyl group,a triazolyl group, a triazolinyl group, a triazolidinyl group, atetrazolyl group, a tetrazolinyl group, a tetrazolidinyl group, adioxolyl group, a dioxolanyl group, a dithiolyl group, a dithiolanylgroup, a pyridyl group, a dihydropyridyl group, a tetrahydropyridylgroup, a piperidinyl group, a pyrimidyl group, a dihydropyrimidyl group,a tetrahydropyrimidyl group, a hexahydropyrimidyl group, a pyridazinylgroup, a dihydropyridazinyl group, a tetrahydropyridazinyl group, ahexahydropyridazinyl group, a pyrazinyl group, a dihydropyrazinyl group,a tetrahydropyrazinyl group, a piperazinyl group, a pyranyl group, adihydropyranyl group, a tetrahydropyranyl group, a dioxynyl group, adioxenyl group, a dioxanyl group, a dithianyl group or a morpholylgroup; a condensed type polynuclear heterocyclic group such as athienothienyl group, a dihydrocyclopentathienyl group, an indolyl group,a tetrahydroindolyl group, an isoindolyl group, a tetrahydroisoindolylgroup, a benzothienyl group, a tetrahydrobenzothienyl group, abenzofuranyl group, a tetrahydrobenzofuranyl group, a benzoxazolylgroup, a tetrahydrobenzoxazolyl group, a benzoisoxazolyl group, atetrahydrobenzoisoxazolyl group, a benzothiazolyl group, atetrahydrobenzothiazolyl group, a benzoisothiazolyl group, atetrahydrobenzoisothiazolyl group, a benzoimidazolyl group, atetrahydrobenzoimidazolyl group, a benzodioxolyl group, a benzodithiolylgroup, a benzodioxanyl group, a benzodithianyl group, a quinolyl group,an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, aphthalazinyl group, a naphthylidinyl group or a purinyl group; or acrosslinked type polynuclear heterocyclic ring such as a quinuclidinylgroup.

The substituent(s) for the alkyl group which may be substituted, thealkenyl group which may be substituted and the alkynyl group which maybe substituted, contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ inthe above formula (I); for the amino group which may be substituted,contained in R², R³, R⁴, R⁵ and R⁶; for the carbonyl group which may besubstituted, contained in R⁸ and R⁹; for the alkoxy group which may besubstituted, contained in R⁴, R⁵, R⁶, R⁸ and R⁹; and for the alkylthiogroup which may be substituted, contained in R⁸ and R⁹, may, forexample, be a halogen atom, an alkoxy group, a haloalkoxy group, analkylthio group, an alkenyloxy group, an alkynyloxy group, analkenylthio group, an alkynylthio group, a cycloalkyl group, acycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, acycloalkylthio group, a cycloalkenylthio group, an alkoxycarbonyl group,an alkylcarbonyl group, an alkylcarbonyloxy group, an alkenyloxycarbonylgroup, an alkynyloxycarbonyl group, an aryloxycarbonyl group, aheteroaryloxycarbonyl group, an alkenylcarbonyl group, analkynylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonylgroup, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, anarylcarbonyloxy group, a heteroarylcarbonyloxy group, an aryl group, aheteroaryl group, an aryloxy group, an arylthio group, an amino group,an amino group which is substituted by an alkyl group, an amino groupwhich is substituted by an alkenyl group, an amino group which issubstituted by an alkynyl group, an amino group which is substituted bya cycloalkyl group, an amino group which is substituted by acycloalkenyl group, an amino group which is substituted by an arylgroup, an amino group which is substituted by a heteroaryl group, anamino group which is substituted by an acyl group, an amino group whichis substituted by an alkylsulfonyl group, an amino group which issubstituted by an arylsulfonyl group, an amino group which issubstituted by a heteroarylsulfonyl group, a cyano group, an acyl group,a nitro group, a carboxyl group, an aminocarbonyl group, ahydroxyaminocarbonyl group, a sulfonyl group, an alkylsulfonyl group, anarylsulfonyl group and a heteroarylsulfonyl group. The number of suchsubstituent(s) or substituent(s) of such substituent(s) may be one ortwo or more, and such substituents may be the same or different.

The substituent(s) for the cycloalkyl group which may be substituted,the cycloalkenyl group which may be substituted, the aryl group whichmay be substituted and the heterocyclic group which may be substituted,contained in R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in the above formula(I), and for the aryloxy group which may be substituted, contained inR⁴, R⁵, R⁸ and R⁹, may, for example, be a halogen atom, an alkyl group,a haloalkyl group, an alkenyl group, an alkynyl group, a heteroarylgroup, an alkoxy group, a haloalkoxy group, an alkoxyalkoxy group, analkylthio group, an alkenyloxy group, an alkynyloxy group, analkenylthio group, an alkynylthio group, a cycloalkyl group, acycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, acycloalkylthio group, a cycloalkenylthio group, an alkoxycarbonyl group,an alkylcarbonyl group, an alkylcarbonyloxy group, an alkenyloxycarbonylgroup, an alkynyloxycarbonyl group, an aryloxycarbonyl group, aheteroaryloxycarbonyl group, an alkenylcarbonyl group, analkynylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonylgroup, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, anarylcarbonyloxy group, a heteroarylcarbonyloxy group, an aryl group, anaryloxy group, a heteroaryloxy group, an arylthio group, aheteroarylthio group, an amino group, an amino group which issubstituted by an alkyl group, an amino group which is substituted by analkenyl group, an amino group which is substituted by an alkynyl group,an amino group which is substituted by a cycloalkyl group, an aminogroup which is substituted by a cycloalkenyl group, an amino group whichis substituted by an aryl group, an amino group which is substituted bya heteroaryl group, an amino group which is substituted by an acylgroup, an amino group which is substituted by an alkylsulfonyl group, anamino group which is substituted by an arylsulfonyl group, an aminogroup which is substituted by a heteroarylsulfonyl group, a cyano group,an acyl group, a nitro group, a carboxyl group, an aminocarbonyl group,a hydroxyaminocarbonyl group, a sulfonyl group, an alkylsulfonyl group,an arylsulfonyl group, a heteroarylsulfonyl group and an arylalkylgroup. The number of such substituent(s) or substituent(s) attached tosuch substituent(s) may be one or two or more, and such substituents maybe the same or different.

Among the compounds represented by the above formula (I) or saltsthereof, a nitroetheneamine derivative represented by the formula (I-1):

wherein

R^(1′) is a hydrogen atom, an alkyl group which may be substituted, analkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted or a cyano group;

each of R^(2′) and R^(3′) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted (provided that aheterocyclic methyl group which may be substituted, is excluded), acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted or a —A′—R^(7′) group(wherein A′ is S, SO, SO₂, SO₃, CO or CO₂, and R^(7′) is a hydrogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted); or R^(2′) and R^(3′) mayform, together with the N atom, a N═CR^(8′)R^(9′) group (wherein each ofR^(8′) and R^(9′) which are independent of each other, is a hydrogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted, a cyano group, a nitrogroup, an alkoxy group which may be substituted, an aryloxy group whichmay be substituted or a —A′—R⁷ group (wherein A′ and R^(7′) are asdefined above));

R^(4′) is an alkyl group which may be substituted, a cycloalkyl groupwhich may be substituted, a cycloalkenyl group which may be substituted,an aryl group which may be substituted, an alkoxy group which may besubstituted, a —A′—R^(7′) group (wherein A′ and R^(7′)are as definedabove) or an amino group which may be substituted;

R^(5′) is a hydrogen atom, an alkyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, an alkoxygroup which may be substituted, a —A′—R^(7′) group (wherein A′ andR^(7′) are as defined above) or an amino group which may be substituted;or R^(4′) and R^(5′) may form, together with the N atom, aN═CR^(8′)R^(9′) group (wherein R^(8′) and R^(9′) are as defined above);

R^(6′) is a hydrogen atom, a nitro group, a cyano group, a —A′—R^(7′)group (wherein A′ and R^(7′) are as defined above), an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted, a heterocyclic group which may besubstituted, an alkoxy group which may be substituted, a halogen atom oran amino group which may be substituted; and further

at least two selected from R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) maytogether form a ring containing or not containing a hetero atom;

provided that (1) a case where R^(1′) or R^(4′) is an alkyl groupsubstituted by a hetero-ring which may be substituted, (2) a case whereR^(1′), R^(2′), R^(3′), R^(5′) and R^(6′) are all hydrogen atoms andR^(4′) is

(wherein R^(10′) is a hydrogen atom, a halogen atom, an alkyl group, analkoxy group or a dialkylamino group) and (3) a case where R^(1′),R^(3′), R^(5′) and R^(6′) are all hydrogen atoms, and R^(2′) is ahydrogen atom, an alkyl group which may be substituted or an aryl groupwhich may be substituted, and R^(4′) is

(wherein j is an integer of from 1 to 6), are excluded; or a saltthereof, is a compound which heretofore has not specifically been known.

Among the nitroetheneamine derivatives represented by the above formula(I-1) or salts thereof, as compounds which heretofore have notspecifically been known, a nitroetheneamine derivative wherein R¹ is ahydrogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted or a cyano group;

each of R^(2′) and R^(3′) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted (provided that aheterocyclic methyl group which may be substituted, is excluded), acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, a heterocyclic group which may be substituted or a—A′—R^(7′) group (wherein A′ is S, SO, SO₂, SO₃, CO or CO₂, and R^(7′)is a hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted); or R^(2′) and R^(3′)may form, together with the N atom, a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted);

R^(4′) s an alkyl group which may be substituted, an alkoxyphenyl group,a haloalkyloxyphenyl group, a cycloalkyl group which may be substituted,a cycloalkenyl group which may be substituted, an alkoxy group which maybe substituted, a —A′—R^(7′) group (wherein A′ and R^(7′) are as definedabove) or an amino group which may be substituted;

R^(5′) is a hydrogen atom, an alkyl group, an alkoxyphenyl group, ahaloalkyloxyphenyl group, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an alkoxy group which maybe substituted, a —A′—R^(7′) group (wherein A′ and R^(7′) are as definedabove) or an amino group which may be substituted;

R^(6′) is a hydrogen atom, a nitro group, a cyano group or a —A′—R^(7′)group (wherein A′ and R^(7′) are as defined above) or an alkyl groupwhich may be substituted;

or R^(4′) and R^(5′) may form, together with the N atom, aN═CR^(8″)R^(9″) group (wherein R^(8″) and R^(9″) are as defined above);and further

at least two selected from R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) maytogether form a ring containing or not containing a hetero atom;

provided that (1) a case where R^(1′) or R^(4′) is an alkyl groupsubstituted by a hetero-ring which may be substituted, (2) a case whereR^(1′), R^(3′), R^(5′) and R^(6′) are all hydrogen atoms, R^(2′) is ahydrogen atom, an alkyl group which may be substituted or an aryl groupwhich may be substituted, and R^(4′) is

(wherein j is an integer of from 1 to 6), and (3) a case wherein R^(1′)is a hydrogen atom; each of R^(2′) and R^(3′) which are independent ofeach other, is a hydrogen atom, an alkyl group which may be substitutedor a phenyl group which may be substituted; R^(4′) is an alkyl which maybe substituted, a phenyl group which may be substituted, a —A′—R^(7′)group (wherein A′ and R^(7′) are as defined above) or an amino groupwhich may be substituted; R^(5′) is a hydrogen atom, an alkyl groupwhich may be substituted or a phenyl group which may be substituted; andR^(6′) is a hydrogen atom, are excluded; or a salt thereof, is apreferred compound.

Among the above-mentioned preferred compounds of the formula (I-1), anitroetheneamine derivative wherein R^(1′) is a hydrogen atom; R² is ahydrogen atom, a heterocyclic group which may be substituted or a—A″—R^(7″) group (wherein A″ is CO, CO₂ or SO₂, and R^(7″) is an alkylgroup which may be substituted or an aryl group which may besubstituted); R^(3′) is a hydrogen atom, an alkyl group which may besubstituted (provided that a heterocyclic methyl group which may besubstituted, is excluded), a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ and R^(7″) are as defined above); orR^(2′) and R^(3′) may together form, a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted); R^(4′) is an alkyl groupwhich may be substituted (provided that a heterocyclic alkyl group whichmay be substituted, is excluded), an alkoxyphenyl group, ahaloalkyloxyphenyl group, a cycloalkyl group which may be substituted,an alkylsulfonyl group which may be substituted, an alkenylsulfonylgroup which may be substituted, an alkynylsulfonyl group which may besubstituted, a cycloalkylsufonyl group which may be substituted, acycloalkenylsulfonyl group which may be substituted, an arylsulfonylgroup which may be substituted, a sulfonyl group substituted by a heteroring which may be substituted or an amino group which may besubstituted; R^(5′) is a hydrogen atom; R^(6′) is a hydrogen atom or analkyl group; and further R^(2′) and R^(3′) may together form a ringcontaining or not containing a hetero atom; provided that (1) a casewhere R^(1′), R^(2′), R^(5′) and R^(6′) are hydrogen atoms; R^(3′) is ahydrogen atom or an alkyl group which may be substituted; R^(4′) is analkyl which may be substituted, an alkoxyphenyl group which may besubstituted, a haloalkyloxyphenyl group which may be substituted, analkylsulfonyl group which may be substituted, an alkenylsulfonyl groupwhich may be substituted, an alkynylsulfonyl group which may besubstituted, a cycloalkylsufonyl group which may be substituted, acycloalkenylsulfonyl group which may be substituted, an arylsulfonylgroup which may be substituted or a sulfonyl group substituted by ahetero ring which may be substituted, and (2) a case where R^(1′),R^(3′), R^(5′) and R^(6′) are hydrogen atoms, R^(2′) is a heterocyclicgroup (provided that a heterocyclic group substituted by at least onehalogen atom, is excluded), and R^(4′) is an alkyl group which may besubstituted, are excluded; or a salt thereof, is a novel compound.

The above novel compound is a compound particularly excellent as anactive constituent for a matrix metalloproteinase inhibitor and can beused as an active constituent for a medical composition such as {circlearound (1)} an inhibitor against at least one matrix metalloproteinaseselected from MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, particularly a MMP-9inhibitor; {circle around (2)} an angiogenesis inhibitor; {circle around(3)} an anticancer drug; {circle around (4)} a tumor cell infiltrationinhibitor; {circle around (5)} a tumor metastatis inhibitor; or {circlearound (6)} a therapeutic or preventive agent for rheumatoid arthritis.Among these novel compounds, the following compounds are particularlyexcellent as active constituents for matrix metalloproteinaseinhibitors.

(1) A nitroetheneamine derivative of the above formula (I-1), whereinR^(1′) is a hydrogen atom; R^(2′) is a heterocyclic group which may besubstituted or a —A″″R^(7″) group (wherein A″ is CO, CO₂ or SO₂, andR^(7″) is an alkyl group which may be substituted or an aryl group whichmay be substituted); R^(3′) is a hydrogen atom, an alkyl group which maybe substituted (provided that a heterocyclic methyl group which may besubstituted, is excluded), a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ and R^(7″) are as defined above); orR^(2′) and R^(3′) may together form a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted) or form a ring containingor not containing a hetero atom; R^(4′) is an alkylsulfonyl group whichmay be substituted, an alkenylsulfonyl group which may be substituted,an alkynylsulfonyl group which may be substituted, a cycloalkylsufonylgroup which may be substituted, a cycloalkenylsulfonyl group which maybe substituted, an arylsulfonyl group which may be substituted, asulfonyl group substituted by a hetero ring which may be substituted oran amino group which may be substituted; R^(5′) is a hydrogen atom; andR^(6′) is a hydrogen atom or an alkyl group; or a salt thereof.

(2) A nitroetheneamine derivative of the above formula (I-1), whereinR^(1′) is a hydrogen atom; R^(2′) is a heterocyclic group which may besubstituted or a —A″—R^(7″) group (wherein A″ is CO, CO₂ or SO₂, andR^(7″) is an alkyl group which may be substituted or an aryl group whichmay be substituted); R^(3′) is a hydrogen atom, an alkyl group which maybe substituted (provided that a heterocyclic methyl group which may besubstituted, is excluded), a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ and R^(7″) are as defined above); orR^(2′) and R^(3′) may together form a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted); R^(4′) is an alkylsulfonylgroup which may be substituted, an alkenylsulfonyl group which may besubstituted, an alkynylsulfonyl group which may be substituted, acycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonylgroup which may be substituted, an arylsulfonyl group which may besubstituted, a sulfonyl group substituted by a hetero ring which may besubstituted or an amino group which may be substituted; R^(5′) is ahydrogen atom; and R^(6′) is a hydrogen atom or an alkyl group; or asalt thereof.

(3) A nitroetheneamine derivative of the above formula (I-1), whereinR^(1′) is a hydrogen atom; R^(2′) is a heterocyclic group which may besubstituted or a —A″—R^(7″) group (wherein A″ is CO, CO₂ or SO₂, andR^(7″) is an alkyl group which may be substituted or an aryl group whichmay be substituted); R^(3′) is a hydrogen atom, an alkyl group which maybe substituted (provided that a heterocyclic methyl group which may besubstituted, is excluded), a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ and R^(7″) are as defined above); orR^(2′) and R^(3′) may together form a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted); R^(4′) is an alkylsulfonylgroup which may be substituted, an arylsulfonyl group which may besubstituted, or an amino group which may be substituted; R^(5′) is ahydrogen atom; and R^(6′) is a hydrogen atom or an alkyl group; or asalt thereof.

(4) A nitroetheneamine derivative of the above formula (I-1), whereinR^(1′) is a hydrogen atom; R^(2′) is a heterocyclic group which may besubstituted or a —A″—R^(7″) group (wherein A″ is CO, CO₂ or SO₂, andR^(7″) is an alkyl group which may be substituted or an aryl group whichmay be substituted); R^(3′) is a hydrogen atom or methyl; or R^(2′) andR^(3′) may together form a N═CR^(8″)R^(9″) group (wherein each of R^(8″)and R^(9″) which are independent of each other, is a hydrogen atom, analkyl group which may be substituted, an aryl group which may besubstituted, a heterocyclic group which may be substituted or an alkoxygroup which may be substituted); R^(4′) is an alkylsulfonyl group whichmay be substituted, an arylsulfonyl group which may be substituted, oran amino group which may be substituted; R^(5′) is a hydrogen atom; andR^(6′) is a hydrogen atom or an alkyl group; or a salt thereof.

(5) A nitroetheneamine derivative of the formula (I-1), wherein R^(1′)is a hydrogen atom; R^(2′) and R^(3′) may together form a ringcontaining or not containing a hetero atom; R^(4′) is an alkyl groupwhich may be substituted, an alkoxyphenyl group, a haloalkyloxyphenylgroup, a cycloalkyl group which may be substituted, an alkylsulfonylgroup which may be substituted, an alkenylsulfonyl group which may besubstituted, an alkynylsulfonyl group which may be substituted, acycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonylgroup which may be substituted, an arylsulfonyl group which may besubstituted or a sulfonyl group substituted by a hetero ring which maybe substituted; R^(5′) is a hydrogen atom; and R^(6′) is a hydrogen atomor an alkyl group; or a salt thereof.

(6) A nitroetheneamine derivative of the formula (I-1), wherein R^(1′)is a hydrogen atom; R^(2′) and R^(3′) may together form a ringcontaining or not containing a hetero atom; R^(4′) is an alkylsulfonylgroup which may be substituted or an arylsulfonyl group which may besubstituted; R^(5′) is a hydrogen atom; and R^(6′) is a hydrogen atom oran alkyl group; or a salt thereof.

The compound of the above formula (I) or a salt thereof can be producedby a known process for producing similar compounds (such as the processdisclosed in JP-A-2-171) or a process similar thereto. However, aspreferred embodiments, the following processes 1 to 12 may beexemplified.

(1) Process 1

A process for producing a nitroetheneamine derivative of the aboveformula (I), which comprises:

(1) a first step of reacting a compound represented by the formula (II):

wherein Z is an alkyl group or an arylalkyl group, and R⁶ is as definedabove, with a compound represented by the formula (III):

wherein Y is hydrogen or an alkali metal element, and R⁴ and R⁵ are asdefined above, to obtain a compound represented by the formula (IV):

wherein Z, R⁴, R⁵ and R⁶ are as defined above, and

(2) a second step of reacting the compound of the above formula (IV)obtained in the first step, with a compound represented by the formula(V):

wherein Y is hydrogen or an alkali metal element, and R¹, R² and R³ areas defined above, to obtain a nitroetheneamine derivative of the aboveformula (I).

(2) Process 2

A process for producing a nitroetheneamine derivative of the aboveformula (I), which comprises:

(1) a first step of reacting a compound of the above formula (II) with acompound of the above formula (V) to obtain a compound of the formula(VI):

wherein Z, R¹, R², R³ and R⁶ are as defined above, and

(2) a second step of reacting the above compound of the above formula(VI) obtained in the first step, with a compound of the formula (III) toobtain a nitroetheneamine derivative of the above formula (I).

Here, the compound of the above formula (II) and the compound of theabove formula (III) as the starting materials for Process 1 and Process2 can be produced by known processes or processes similar thereto.

The respective reactions in Process 1 and Process 2 can be carried outin the presence of a suitable solvent. The solvent to be specificallyused, may, for example, be an alcohol such as methanol, ethanol,propanol or butanol; an aromatic hydrocarbon such as benzene, toluene orxylene; an aliphatic hydrocarbon such as pentane, hexane, heptane,petroleum ether, ligroin or petroleum benzin; an ether such as diethylether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; anitrile such as acetonitrile or propionitrile; an acid amide such asdimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amidesuch as hexamethylphosphoramide; a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane;and a solvent mixture thereof.

In order to carry out the respective reactions in Process 1 and Process2 efficiently, it is preferred to carry out the reactions in thepresence of a base. The base to be specifically used, may, for example,be an organic base such as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as 15 lithium hydrogencarbonate,sodium hydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride; oran alkoxide such as sodium methoxide, sodium ethoxide or potassiumt-butoxide. Further, the compound of the above formula (III) and/or thecompound of the above formula (V) will also act as a base.

The respective reactions in Process 1 and Process 2 are carried outusually at a reaction temperature of from −30 to 150° C., preferably ata reaction temperature of from 0 to 100° C. The reaction time is usuallyfrom 0.1 to 48 hours.

In the first step of Process 1, the compound of the above formula (III)can be used in an amount of from 1 to 1.2 equivalents per mol of thecompound of the above formula (II). If the compound of the above formula(III) is used excessively, in addition to the compound of the aboveformula (IV), a compound represented by the formula (VII):

wherein R⁴, R⁵ and R⁶ are as defined above, will be formed as aby-product, such being undesirable. Further, in the second step ofProcess 1, the compound of the above formula (V) can be used in anamount of from 1 to 1.5 equivalents per mol of the compound of the aboveformula (IV), but it may be used excessively without any particularproblem.

In the first step of Process 2, the compound of the above formula (V)can be used in an amount of from 1 to 1.2 equivalents per mol of thecompound of the above formula (II). If the compound of the above formula(V) is used excessively, in addition to the compound of the aboveformula (VI), a compound represented by the formula (VIII):

wherein R¹, R², R³ and R⁶ are as defined above, will be produced as aby-product, such being undesirable. Further, in the second step ofProcess 2, the compound of the above formula (III) can be used in anamount of from 1 to 1.5 equivalents per mol of the compound of the aboveformula (VI), but it may be used excessively without any particularproblem.

The compound of the above formula (IV) obtained in Process 1 and thecompound of the above formula (VI) obtained in Process 2, may besupplied to the subsequent reaction for producing a compound of theabove formula (I) directly in the form of the reaction mixture or afterseparation and purification by a known means such as concentration,concentration under reduced pressure, solvent extraction,recrystallization or chromatography.

Various reaction conditions in Process 1 i.e. (1) the type and/or theamount of the compound of the above formula (II), (2) the type and/orthe amount of the compound of the above formula (III), (3) with orwithout use of a solvent in the reaction of the first step, (4) the typeand/or the amount of the solvent in the reaction of the first step, (5)with or without use of a base in the reaction of the first step, (6) thetype and/or the amount of the base in the reaction of the first step,(7) the reaction temperature in the first step, (8) the reaction time inthe first step, (9) the type of the compound of the above formula (IV)as an intermediate product in the first step, (10) with or withoutseparation and purification of the compound of the above formula (IV),(11) the type and/or the amount of the compound of the formula (V), (12)with or without use of a solvent in the reaction of the second step,(13) the type and/or the amount of the solvent in the reaction of thesecond step, (14) with or without use of a base in the reaction of thesecond step, (15) the type and/or the amount of the base in the reactionof the second step, (16) the reaction temperature in the reaction of thesecond step, (17) the reaction time in the reaction of the second step,and (18) the type of the compound of the formula (I) as the finaldesired product, may mutually suitably be combined. Further, among thesevarious reaction conditions, there are some which have a reactioncondition of a usual range and a reaction condition of a preferredrange, and they may also mutually suitably be selected and combined.

Combinations of the above-mentioned various reaction conditions are alsoin the scope of Process 1.

Various reaction conditions in Process 2 i.e. (1) the type and/or theamount of the compound of the above formula (II), (2) the type and/orthe amount of the compound of the above formula (V), (3) with or withoutuse of a solvent in the reaction of the first step, (4) the type and/orthe amount of the solvent in the reaction of the first step, (5) with orwithout use of a base in the reaction of the first step, (6) the typeand/or the amount of the base in the reaction of the first step, (7) thereaction temperature in the first step, (8) the reaction time in thefirst step, (9) the type of the compound of the above formula (VI) as anintermediate product in the first step, (10) with or without separationand purification of the compound of the above formula (VI), (11) thetype and/or the amount of the compound of the formula (III), (12) withor without use of a solvent in the reaction of the second step, (13) thetype and/or the amount of the solvent in the reaction of the secondstep, (14) with or without use of a base in the reaction of the secondstep, (15) the type and/or the amount of a base in the reaction of thesecond step, (16) the reaction temperature in the reaction of the secondstep, (17) the reaction time in the reaction of the second step, and(18) the type of the compound of the formula (I) as the final desiredproduct, may mutually suitably be combined. Further, among these variousreaction conditions, there are some which have a reaction condition of ausual range and a reaction condition of a preferred range, and they mayalso mutually suitably be selected and combined.

Combinations of the above various reaction conditions are also in thescope of Process 2.

(3) Process 3

A process for producing a nitroetheneamine derivative of the aboveformula (I), which comprises:

(1) a first step of reacting a compound represented by the formula (IX):

wherein X is a halogen atom, and R⁶ is as defined above, and/or acompound represented by the formula (X): O₂N—CH(R⁶)CX₃, wherein X and R⁶are as defined above, with a compound of the above formula (III) toobtain a compound represented by the formula (XI):

wherein X, R⁴, R⁵ and R⁶ are as defined above, and

(2) a second step of reacting a compound of the above formula (XI)obtained in the first step, with a compound of the above formula (V) toobtain a nitroetheneamine derivative of the above formula (I).

(4) Process 4

A process for producing a nitroetheneamine derivative of the aboveformula (I) which comprises:

(1) a first step of reacting a compound of the above formula (IX) and/ora compound of the above formula (X), with a compound of the aboveformula (V) to obtain a compound represented by the formula (XII):

wherein X, R¹, R², R³ and R⁶ are as defined above, and

(2) a second step of reacting the compound of the above formula (XII)obtained in the first step with a compound of the above formula (III) toobtain a nitroetheneamine derivative of the above formula (I).

Further, the compound of the above formula (IX) and the compound of theabove formula (X) which are the starting materials in Process 3 andProcess 4, can be produced by a known method disclosed, for example, inJournal of Organic Chemistry, Vol. 25, 1312 (1960) or a method similarthereto.

The respective reactions of Process 3 and Process 4 can be carried outin the presence of a suitable solvent. The solvent to be specificallyused, may, for example, be an aromatic hydrocarbon such as benzene,toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane,heptane, petroleum ether, ligroin or petroleum benzin; an ether such asdiethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran ordioxane; a nitrile such as acetonitrile or propionitrile; an acid amidesuch as dimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amidesuch as hexamethylphosphoramide; a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane;and a solvent mixture thereof.

In Process 3 and Process 4, in order to carry out the respectivereactions efficiently, it is preferred to carry out the reaction in thepresence of a base. The base to be specifically used, may, for example,be an organic base such as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride; oran alkoxide such as sodium methoxide, sodium ethoxide or potassiumt-butoxide. Further, the compound of the above formula (III) and/or thecompound of the above formula (V) also acts as a base.

The respective reactions of Process 3 and Process 4 are carried outusually at a reaction temperature of from −30 to 150° C., preferably ata reaction temperature of from 0 to 80° C. The reaction time is usuallyfrom 0.1 to 48 hours.

In the first step of Process 3, the compound of the above formula (III)can be used in an amount of from 0.8 to 2 equivalents, preferably from 1to 1.2 equivalents, per mol of the compound of the above formula (IX).Further, in the second step of Process 3, the compound of the aboveformula (III) can be used in an amount of from 1 to 1.5 equivalents permol of the compound of the above formula (XI). However, it may be usedexcessively without any particular problem.

In the first step of Process 4, the compound of the above formula (V)can be used in an amount of from 1 to 2 equivalents, preferably from 1to 1.2 equivalents, per mol of the compound of the above formula (IX).Further, in the second step of Process 4, the compound of the aboveformula (III) can be used in an amount of from 1 to 1.5 equivalents permol of the compound of the above formula (XII). However, it may be usedexcessively without any particular problem.

The compound of the above formula (XI) obtained in Process 3, and thecompound of the above formula (XII) obtained in Process 4, may besupplied to the subsequent reaction for producing the compound of theabove formula (I) directly in the form of the reaction mixture or afterseparation and purification by a known means such as concentration,concentration under reduced pressure, solvent extraction,recrystallization or chromatography.

Various reaction conditions in Process 3 i.e. (1) the type of thecompound of the above formula (IX) and/or the compound of the aboveformula (X), (2) the amount of the compound of the above formula (IX)and the compound of the above formula (X), (3) the type and/or theamount of the compound of the above formula (III), (4) with or withoutuse of a solvent in the reaction of the first step, (5) the type and/orthe amount of the solvent in the reaction in the first step, (6) with orwithout use of a base in the reaction of the first step, (7) the typeand/or the amount of a base in the reaction of the first step, (8) thereaction temperature in the first step, (9) the reaction time in thefirst step, (10) the type of the compound of the above formula (XI)which is an intermediate product in the first step, (11) with or withoutseparation and purification of the compound of the above formula (XI),(12) the type and/or the amount of the compound of the formula (V), (13)with or without use of a solvent in the reaction of the second step,(14) the type and/or the amount of the solvent in the reaction of thesecond step, (15) with or without use of a base in the reaction of thesecond step, (16) the type and/or the amount of the base in the reactionof the second step, (17) the reaction temperature in the reaction of thesecond step, (18) the reaction time in the reaction of the second step,and (19) the type of the compound of the formula (I) as the finaldesired product, may mutually suitably be combined. Further, among thesevarious reaction conditions, there are some which have a reactioncondition of a usual range and a reaction condition of a preferredrange, and they may also mutually suitably be selected and combined.

Combinations of the above various reaction conditions are also withinthe scope of Process 3.

Various reaction conditions in Process 4 i.e. (1) the type of thecompound of the above formula (IX) and/or the compound of the aboveformula (X), (2) the amount of the compound of the above formula (IX)and the compound of the above formula (X), (3) the type and/or theamount of the compound of the above formula (V), (4) with or without useof a solvent in the reaction of the first step, (5) the type and/or theamount of the solvent in the reaction of the first step, (6) with orwithout use of a base in the reaction of the first step, (7) the typeand/or the amount of a base in the reaction of the first step, (8) thereaction temperature in the first step, (9) the reaction time in thefirst step, (10) the type of the compound of the above formula (XII)which is an intermediate product in the first step, (11) with or withoutseparation and purification of the compound of the above formula (XII),(12) the type and/or the amount of the compound of the formula (III),(13) with or without use of a solvent in the reaction of the secondstep, (14) the type and/or the amount of the solvent in the reaction ofthe second step, (15) with or without use of a base in the reaction ofthe second step, (16) the type and/or the amount of the base in thereaction of the second step, (17) the reaction temperature in thereaction of the second step, (18) the reaction time in the reaction ofthe second step, and (19) the type of the compound of the formula (I) asthe final desired product, may mutually suitably be combined. Further,among these various reaction conditions, there are some which have areaction condition of a usual range and a reaction condition of apreferred range, and they may also mutually suitably be selected andcombined.

Combination of the above various reaction conditions are also within thescope of Process 4.

(5) Process 5

A process for producing a nitroetheneamine derivative of theafter-mentioned formula (I′), which comprises:

(1) a first step of reacting a compound represented by the above formula(V) with a compound represented by the formula (XIII): R⁴—NCS, whereinR⁴ is as defined above, to obtain a compound represented by the formula(XIV):

wherein R¹, R², R³ and R⁴ are as defined above, and

(2) a second step of reacting the compound of the above formula (XIV)obtained in the first step with a compound of the formula (XV): Z—Xwherein Z and X are as defined above, to obtain a compound of theformula (XVI):

wherein Z, R¹, R², R³ and R⁴ are as defined above, and

(3) a third step of reacting the compound of the above formula (XVI)obtained in the second step with a compound represented by the formula(XVII): R⁶—CH₂NO₂, wherein R⁶ is as defined above, to obtain anitroetheneamine derivative of the formula (I′):

wherein R¹, R², R³, R⁴ and R⁶ are as defined above.

Here, the compound of the above formula (I′) is a compound of the aboveformula (I), and a compound where R⁵ is a hydrogen atom.

The reaction in the first step of Process 5 can be carried out in thepresence of a suitable solvent. The solvent to be specifically used,may, for example, be an alcohol such as methanol, ethanol, propanol orbutanol; an aromatic hydrocarbon such as benzene, toluene or xylene; analiphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether,ligroin or petroleum benzin; an ether such as diethyl ether, dipropylether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such asacetonitrile or propionitrile; an acid amide such as dimethylformamideor dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfonesuch as sulfolane; a phosphoric acid amide such ashexamethylphosphoramide; a halogenated hydrocarbon such as chloroform,dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and asolvent mixture thereof.

In the first step of Process 5, in order to carry out the reactionefficiently, it is preferred to carry out the reaction in the presenceof a base. The base to be specifically used, may, for example, be anorganic base such as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal carbonate such as lithium carbonate, sodium carbonate or potassiumcarbonate; or an alkali metal hydrogencarbonate such as lithiumhydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate. Further, the compound of the above formula (V) alsoacts as a base.

The reaction in the first step of Process 5 is carried out usually at areaction temperature of from −30 to 200° C., preferably at a reactiontemperature of from 0 to 150° C. The reaction time is usually from 0.1to 48 hours.

In the first step of Process 5, the compound of the above formula (XIII)is used in an amount of from 0.8 to 2 equivalents, preferably from 1 to1.2 equivalents, per mol of the compound of the above formula (V). Theobtained compound of the above formula (XIV) may be supplied to thereaction of the second step directly in the form of the reaction mixtureor after separation and purification by a known means such asconcentration, concentration under reduced pressure, solvent extraction,recrystallization or chromatography.

The reaction in the second step of Process 5 can be carried out in thepresence of a suitable solvent. The solvent to be specifically used,may, for example, be an alcohol such as methanol, ethanol, propanol orbutanol; a ketone such as acetone, methyl ethyl ketone, dimethyl ketoneor diethyl ketone; an ester such as methyl acetate, ethyl acetate, butylacetate, methyl formate, ethyl formate, butyl formate or ethylpropionate; an aromatic hydrocarbon such as benzene, toluene or xylene;an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleumether, ligroin or petroleum benzin; an ether such as diethyl ether,dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrilesuch as acetonitrile or propionitrile; an acid amide such asdimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amidesuch as hexamethylphosphoramide; a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane;and a solvent mixture thereof.

In the second step of Process 5, in order to carry out the reactionefficiently, it is preferred to carry out the reaction in the presenceof a base. The base to be specifically used may, for example, be anorganic base such as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride; oran alkoxide such as sodium methoxide, sodium ethoxide or potassiumt-butoxide.

The reaction in the second step of Process 5 is carried out usually at atemperature of from −30 to 150° C., preferably at a temperature of from0 to 100° C. The reaction time is usually from 0.1 to 48 hours.

In the reaction of the second step in Process 5, the compound of theabove formula (XV) can be used in an amount of at least 1 equivalent permol of the compound of the above formula (XIV). As the compound of theabove formula (XV), various compounds may be employed. For example,benzyl bromide or methyl iodide may be employed. The obtained compoundof the above formula (XVI) may be supplied to the reaction of the thirdstep directly in the form of the reaction mixture or after separationand purification by a known means such as concentration, concentrationunder reduced pressure, solvent extraction, recrystallization orchromatography.

The reaction of the third step in Process 5 can be carried out in thepresence of a suitable solvent. The solvent to be specifically used may,for example, be an alcohol such as methanol, ethanol, propanol orbutanol; an aromatic hydrocarbon such as benzene, toluene or xylene; analiphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether,ligroin or petroleum benzin; an ether such as diethyl ether, dipropylether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such asacetonitrile or propionitrile; an acid amide such as dimethylformamideor dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfonesuch as sulfolane; a phosphoric acid amide such ashexamethylphosphoramide; a halogenated hydrocarbon such as chloroform,dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and asolvent mixture thereof.

In the third step of Process 5, in order to carry out the reactionefficiently, it is preferred to carry out the reaction in the presenceof a base. The base to be specifically used may, for example, be anorganic base such as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride; oran alkoxide such as sodium methoxide, sodium ethoxide or potassiumt-butoxide.

The reaction in the third step of Process 5 can be carried out usuallyat a reaction temperature of from −30 to 200° C., preferably at areaction temperature of from 0 to 150° C. The reaction time is usuallyfrom 0.1 to 48 hours.

In the reaction of the third step in Process 5, the compound of theabove formula (XVII) can be used in an amount of from 1 to 5 equivalentsper mol of the compound of the above formula (XVI).

Various reaction conditions in Process 5 i.e. (1) the type and/or theamount of the compound of the formula (V), (2) the type and/or theamount of the compound of the formula (XIII), (3) with or without use ofa solvent in the reaction of the first step, (4) the type and/or theamount of the solvent in the reaction of the first step, (5) with orwithout use of a base in the reaction of the first step, (6) the typeand/or the amount of the base in the reaction of the first step, (7) thereaction temperature of the first step, (8) the reaction time of thefirst step, (9) the type of the compound of the above formula (XIV)which is an intermediate product in the first step, (10) with or withoutseparation and purification of the compound of the formula (XIV) whichis an intermediate product in the first step, (11) the type and/or theamount of the compound of the formula (XV), (12) with or without use ofa solvent in the reaction of the second step, (13) the type and/or themount of the solvent in the reaction of the second step, (14) with orwithout use of a base in the reaction of the second step, (15) the typeand/or the amount of the base in the reaction of the second step, (16)the reaction temperature of the second step, (17) the reaction time ofthe second step, (18) the type of the compound of the above formula(XVI) which is an intermediate product in the second step, (19) with orwithout separation and purification of the compound of the formula (XVI)which is an intermediate product in the second step, (20) the typeand/or the amount of the compound of the formula (XVII), (21) with orwithout use of a solvent in the reaction of the third step, (22) thetype and/or the amount of the solvent in the reaction of the third step,(23) with or without use of a base in the reaction of the second step,(24) the type and/or the amount of a base in the reaction of the secondstep, (25) the reaction temperature of the third step, (26) the reactiontime of the third step, and (27) the type of the compound of the formula(I′) as the final desired product, may mutually suitably be combined.Further, among these various reaction conditions, there are some whichhave a reaction condition of a usual range and a reaction condition of areferred range, and they may also mutually suitably be elected andcombined.

Combinations of the above various reaction conditions are also withinthe scope of Process 5.

(6) Process 6

A process for producing a nitroetheneamine derivative of the aboveformula (I), which comprises:

(1) a first step of reacting a compound represented by the formula(XVIII):

wherein R⁴, R⁵ and R⁶ are as defined above, with a halogenating agent toobtain a compound of the above formula (XI), and

(2) a second step of reacting the compound of the above formula (XI)obtained in the first step with a compound of the above formula (V) toobtain a compound of the above formula (I).

(7) Process 7

A process for producing a nitroetheneamine derivative of the aboveformula (I), which comprises:

(1) a first step of reacting a compound represented by the formula(XIX):

wherein R¹, R², R³ and R⁶ are as defined above, with a halogenatingagent to obtain a compound of the above formula (XII), and

(2) a second step of reacting the compound of the above formula (XII)obtained in the first step with a compound of the above formula (III) toobtain a compound of the above formula (I).

Here, the compound of the above formula (XVIII) and the compound of theabove formula (XIX) which are the starting materials in Process 6 andProcess 7, can be produced by a known method or a method similarthereto.

The reactions of the first step of Process 6 and the first step ofProcess 7, are preferably carried out in the presence of a solvent. Thesolvent to be specifically used may, for example, be an aromatichydrocarbon such as benzene, toluene or xylene; an aliphatic hydrocarbonsuch as pentane, hexane, heptane, petroleum ether, ligroin or petroleumbenzin; an ether such as diethyl ether, dipropyl ether, dibutyl ether,tetrahydrofuran or dioxane; a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane;and a solvent mixture thereof. The reaction is preferably carried out ina system where no water is present.

The halogenating agent to be used in the reactions of the first step ofProcess 6 and the first step of Process 7, may, for example, bephosphorus pentachloride, phosphorus oxychloride, phosphorustrichloride, thionyl chloride or oxalyl chloride. The amount is from 1to 10 equivalents, preferably from 1 to 5 equivalents, per mol of thecompound of the above formula (XVIII) or the compound of the aboveformula (XIX). Further, it is preferred to let a base be present tocapture hydrogen chloride formed by this reaction. Such a base may, forexample, be an organic base such as triethylamine, pyridine,N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene orN,N-dimethylaniline.

The reactions of the first step of Process 6 and the first step ofProcess 7 are carried out usually at a reaction temperature of from −30to 200° C., preferably at a reaction temperature of from 0 to 150° C.The reaction time is usually from 0.1 to 48 hours.

The compound of the above formula (XI) obtained in the first step ofProcess 6 and the compound of the above formula (XII) obtained in thefirst step of Process 7, may be supplied to the reaction of the secondstep of Process 6 which is the same reaction as in the second step ofProcess 3 and to the reaction of the second step of Process 7 which isthe same reaction as in the second step of Process 4, directly in theform of the reaction mixtures or after separation and purification by aknown means such as concentration, concentration under reduced pressure,solvent extraction, recrystallization or chromatography.

Various reaction conditions in Process 6 i.e. (1) the type and/or theamount of the compound of the formula (XVIII), (2) the type and/or theamount of the halogenating agent, (3) with or without use of a solventin the reaction of the first step, (4) the type and/or the amount of thesolvent in the reaction of the first step, (5) with or without use of abase in the reaction of the first step, (6) the type and/or the amountof the base in the reaction of the first step, (7) the reactiontemperature of the first step, (8) the reaction time of the first step,(9) the type of the compound of the formula (XI) which is anintermediate product in the first step, (10) with or without separationand purification of the compound of the above formula (XI), (11) thetype and/or the amount of the compound of the formula (V), (12) with orwithout use of a solvent in the reaction of the second step, (13) thetype and/or the amount of the solvent in the reaction of the secondstep, (14) with or without use of a base in the reaction of the secondstep, (15) the type and/or the amount of the base in the reaction of thesecond step, (16) the reaction temperature in the reaction of the secondstep, (17) the reaction time in the reaction of the second step, and(18) the type of the compound of the formula (I) as the final desiredproduct, may mutually suitably be combined. Further, among these variousreaction conditions, there are some which have a reaction condition of ausual range and a reaction condition of a preferred range, and they mayalso mutually suitably be selected and combined.

Combinations of the above various reaction conditions are also withinthe scope of Process 6.

Various reaction conditions in Process 7 i.e. (1) the type and/or theamount of the compound of the formula (XIX), (2) the type and/or theamount of the halogenating agent, (3) with or without use of a solventin the reaction of the first step, (4) the type and/or the amount of thesolvent in the reaction of the first step, (5) with or without use of abase in the reaction of the first step, (6) the type and/or the amountof a base in the reaction of the first step, (7) the reactiontemperature of the first step, (8) the reaction time of the first step,(9) the type of the compound of the formula (XII) which is anintermediate product in the first step, (10) with or without separationand purification of the compound of the above formula (XII), (11) thetype and/or the amount of the compound of the formula (III), (12) withor without use of a solvent in the reaction of the second step, (13) thetype and/or the amount of the solvent in the reaction of the secondstep, (14) with or without use of a base in the reaction of the secondstep, (15) the type and/or the amount of the base in the reaction of thesecond step, (16) the reaction temperature in the reaction of the secondstep, (17) the reaction time in the reaction of the second step, and(18) the type of the compound of the formula (I) as the final desiredproduct, may mutually suitably be combined. Further, among these variousreaction conditions, there are some which have a reaction condition of ausual range and a reaction condition of a preferred range, and they mayalso mutually suitably be selected and combined.

Combinations of the above various reaction conditions are also withinthe scope of Process 7.

(8) Process 8

A process for producing a nitroetheneamine of the above formula (I),which comprises reacting a compound represented by the formula (XX):

wherein R¹, R², R⁴, R⁵ and R⁶ are as defined above, with a compoundrepresented by the formula (XXI): X—R³ wherein R³ and X are as definedabove.

For the reaction of Process 8, it is preferred to carry out the reactionin the presence of a solvent. The solvent to be specifically used may,for example, be an aromatic hydrocarbon such as benzene, toluene orxylene; an aliphatic hydrocarbon such as pentane, hexane, heptane,petroleum ether, ligroin or petroleum benzin; an ether such as diethylether, dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; anitrile such as acetonitrile or propionitrile; an acid amide such asdimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amidesuch as hexamethylphosphoramide; a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane;and a solvent mixture thereof.

In Process 8, in order to carry out the reaction efficiently, it ispreferred to carry out the reaction in the presence of a base. The baseto be specifically used may, for example, be an organic base such astriethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride;n-butyl lithium, lithium diisopropylamide or sodium amide.

The reaction of Process 8 is carried out usually at a reactiontemperature of from −70 to 150° C., preferably at a reaction temperatureof from −50 to 100° C. The reaction time is usually from 0.1 to 48hours.

In Process 8, the compound of the formula (XXI) can be used in an amountof from 0.8 to 2 equivalents, preferably from 1 to 1.5 equivalents, permol of the compound of the above formula (XX).

Various reaction conditions in Process 8 i.e. (1) the type and/or theamount of the compound of the formula (XX), (2) the type and/or theamount of the compound of the formula (XXI), (3) with or without use ofa solvent, (4) the type and/or the amount of the solvent, (5) with orwithout use of a base, (6) the type and/or the amount of the base, (7)the reaction temperature, (8) the reaction time and (9) the type of thecompound of the above formula (I) as the final desired product, maymutually suitably be combined. Further, among these various reactionconditions, there are some which have a reaction condition of a usualrange and a reaction condition of a preferred range, and they may alsomutually suitably be selected and combined.

Combinations of the above various reaction conditions are also in thescope of Process 8.

A compound of the formula (I″):

wherein R¹, R⁴, R⁵, R⁶, R⁸ and R⁹ are as defined above, is a compound ofthe above formula (I) and a compound wherein R² and R³ form togetherwith the N atom a N═CR⁸R⁹ group, wherein R⁸ and R⁹ are as defined above.This compound can be produced by a method as shown by the followingProcess 9.

(9) Process 9

A process for producing a nitroetheneamine of the above formula (I″),which comprises reacting a compound represented by the formula (XXII):

wherein R¹, R⁴, R⁵ and R⁶ are as defined above, with a compoundrepresented by the formula (XXIII):

wherein R⁸ and R⁹ are as defined above.

For the reaction of Process 9, it is preferred to carry out the reactionin the presence of a solvent. The solvent to be specifically used may,for example, be an alcohol such as methanol, ethanol, propanol orbutanol; an aromatic hydrocarbon such as benzene, toluene or xylene; analiphatic hydrocarbon such as pentane, hexane, heptane, petroleum ether,ligroin or petroleum benzin; an ether such as diethyl ether, dipropylether, dibutyl ether, tetrahydrofuran or dioxane; a nitrile such asacetonitrile or propionitrile; an acid amide such as dimethylformamideor dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfonesuch as sulfolane; a phosphoric acid amide such ashexamethylphosphoramide; a halogenated hydrocarbon such as chloroform,dichloromethane, carbon tetrachloride or 1,2-dichloroethane, and asolvent mixture thereof.

In Process 9, in order to carry out the reaction efficiently, it ispreferred to carry out the reaction in the presence of a base. The baseto be specifically used may, for example, be an organic base such astriethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal carbonate such as lithium carbonate, sodium carbonate or potassiumcarbonate; or an alkali metal hydrogencarbonate such as lithiumhydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate.

In Process 9, in order to carry out the reaction efficiently, it ispreferred to carry out the reaction in the presence of a dehydratingagent such as molecular sieves. Further, it is also possible to removeformed moisture out of the reaction system by azeotropy using a suitablesolvent.

The reaction of Process 9 is carried out usually at a reactiontemperature of from −30 to 150° C., preferably at a reaction temperatureof from 0 to 100° C. The reaction time is usually from 0.1 to 48 hours.

In the reaction of Process 9, the compound of the above formula (XXIII)can be used in an amount of from 0.8 to 2 equivalents, preferably from 1to 1.5 equivalents, per mol of the compound of the above formula (XXII).

Various reaction conditions in Process 9 i.e. (1) the type and/or theamount of the compound of the formula (XXII), (2) the type and/or theamount of the compound of the formula (XXIII), (3) with or without useof a solvent, (4) the type and/or the amount of the solvent, (5) with orwithout use of a base, (6) the type and/or the amount of the base, (7)with or without use of a dehydrating agent, (8) the type and/or theamount of the dehydrating agent, (9) the reaction temperature, (10) thereaction time, and (11) the type of the compound of the formula (I″) asthe final desired product, may mutually suitably be combined. Further,among these various reaction conditions, there are some which have areaction condition of a usual range and a reaction condition of apreferred range, and they may also mutually suitably be selected andcombined.

Combinations of the above various reaction conditions are also in thescope of Process 9.

(10) Process 10

A process for producing a nitroetheneamine derivative of the aboveformula (I′), which comprises:

(1) a first step of reacting a compound represented by the formula(XXIV):

wherein R⁴ and Z are as defined above, with a compound of the aboveformula (XVII) to obtain a compound represented by the formula (XXV):

wherein R⁴, R⁶ and Z are as defined above, and

(2) a second step of reacting the compound of the above formula (XXV)obtained in the first step with a compound of the above formula (V) toobtain a nitroetheneamine derivative of the above formula (I′).

(11) Process 11

A process for producing a nitroetheneamine derivative of theafter-mentioned formula (I′″), which comprises:

(1) a first step of reacting a compound represented by the formula(XXVI):

wherein R², R³ and Z are as defined above, with a compound of the aboveformula (XVII) to obtain a compound of the formula (XXVII):

wherein R², R³, R⁶ and Z are as defined above, and

(2) a second step of reacting the compound of the above formula (XVII)obtained in the first step with a compound of the above formula (III) toobtain a nitroetheneamine derivative represented by the formula (I′″):

wherein R², R³, R⁴, R⁵ and R⁶ are as defined above. Here, the compoundof the above formula (I′″) is a compound of the above formula (I) and acompound wherein R′ is a hydrogen atom. Further, the compound of theabove formula (XXIV) and the compound of the above formula (XXVI) whichare the starting materials in Process 10 and Process 11, can be producedby a known method or a method similar thereto.

The reaction in each step of Process 10 and Process 11 can be carriedout in the presence of a suitable solvent. The solvent to bespecifically used may, for example, be an alcohol such as methanol,ethanol, propanol or butanol; an aromatic hydrocarbon such as benzene,toluene or xylene; an aliphatic hydrocarbon such as pentane, hexane,heptane, petroleum ether, ligroin or petroleum benzin; an ether such asdiethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran ordioxane; a nitrile such as acetonitrile or propionitrile; an acid amidesuch as dimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphoric acid amidesuch as hexamethylphosphoramide; a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane;and a solvent mixture thereof.

In Process 10 and Process 11, in order to carry out the reaction of eachstep efficiently, it is preferred to carry out the reaction in thepresence of a base. The base to be specifically used may, for example,be an organic base such as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride; oran alkoxide such as sodium methoxide, sodium ethoxide or potassiumt-butoxide. Further, in the second step of Process 10, the compound ofthe above formula (V) acts also as a base. Further, in the second stepof Process 11, the compound of the above formula (III) acts also as abase.

Each reaction of the first step in Process 10 and the first step inProcess 11 is carried out usually at a reaction temperature of from −30to 150° C., preferably at a reaction temperature of from 0 to 800C. Thereaction time is usually from 0.1 to 48 hours. In the first step ofProcess 10, the compound of the above formula (XVII) can be used in anamount of from 0.8 to 2 equivalents, preferably from 1 to 1.5equivalents, per mol of the compound of the above formula (XXIV).Further, in the first step of Process 11, the compound of the aboveformula (XVII) can be used in an amount of from 0.8 to 2 equivalents,preferably from 1 to 1.5 equivalents, per mol of the compound of theabove formula (XXVI).

Each reaction of the second step in Process 10 and the second step inProcess 11, is carried out usually at a temperature of from −30 to 150°C., preferably at a reaction temperature of from 0 to 80° C. Thereaction time is usually from 0.1 to 48 hours. In the second step ofProcess 10, the compound of the above formula (V) can be used in anamount of from 1 to 1.5 equivalents, per mol of the compound of theabove formula (XXV). Further, in the second step of Process 11, thecompound of the above formula (III) can be used in an amount of from 1to 1.5 equivalents per mol of the compound of the above formula (XXVII).

The compound of the above formula (XXV) obtained in the first step ofProcess 10 and the compound of the above formula (XXVII) obtained in thefirst step of Process 11 may be supplied to the respective reactions inthe second step of Process 10 and in the second step of Process 11directly in the form of the reaction mixtures or after separation andpurification by a known means such as concentration, concentration underreduced pressure, solvent extraction, recrystallization orchromatography.

Various reaction conditions in Process 10 i.e. (1) the type and/or theamount of the compound of the formula (XXIV), (2) the type and/or theamount of the compound of the formula (XVII), (3) with or without use ofa solvent in the reaction of the first step, (4) the type and/or theamount of the solvent in the reaction of the first step, (5) with orwithout use of a base in the reaction of the first step, (6) the typeand/or the amount of the base in the reaction of the first step, (7) thereaction temperature of the first step, (8) the reaction time of thefirst step, (9) the type of the compound of the formula (XXV) which isan intermediate product in the first step, (10) with or withoutseparation and purification of the compound of the above formula (XXV),(11) the type and/or the amount of the compound of the formula (V), (12)with or without use of a solvent in the reaction of the second step,(13) the type and/or the amount of the solvent in the reaction of thesecond step, (14) with or without use of a base in the reaction of thesecond step, (15) the type and/or the amount of the base in the reactionof the second step, (16) the reaction temperature in the reaction of thesecond step, (17) the reaction time in the reaction of the second step,and (18) the type of the compound of the formula (I′) as the finaldesired product, may mutually suitably be combined. Further, among thesevarious reaction conditions, there are some which have a reactioncondition of a usual range and a reaction condition of a preferredrange, and they may also mutually suitably be selected and combined.

Combinations of the above various reaction conditions are also withinthe scope of Process 10.

Various reaction conditions in Process 11 i.e. (1) the type and/or theamount of the compound of the formula (XXVI), (2) the type and/or theamount of the compound of the formula (XVII), (3) with or without use ofa solvent in the reaction of the first step, (4) the type and/or theamount of the solvent in the reaction of the first step, (5) with orwithout use of a base in the reaction of the first step, (6) the typeand/or the amount of the base in the reaction of the first step, (7) thereaction temperature of the first step, (8) the reaction time of thefirst step, (9) the type of the compound of the formula (XXVII) which isan intermediate product in the first step, (10) with or withoutseparation and purification of the compound of the above formula(XXVII), (11) the type and/or the amount of the compound of the formula(III), (12) with or without use of a solvent in the reaction of thesecond step, (13) the type and/or the amount of the solvent in thereaction of the second step, (14) with or without use of a base in thereaction of the second step, (15) the type and/or the amount of the basein the reaction of the second step, (16) the reaction temperature in thereaction of the second step, (17) the reaction time in the reaction ofthe second step, and (18) the type of the compound of the formula (I′″)as A the final desired product, may mutually suitably be combined.Further, among these various reaction conditions, there are some whichhave a reaction condition of a usual range and a reaction condition of apreferred range, and they may also mutually suitably be selected andcombined.

Combinations of the above various reaction conditions are also withinthe scope of Process 11.

(12) Process 12

A process for producing a nitroetheneamine derivative of the aboveformula (I′), which comprises:

(1) a first step of reacting a compound represented by the above formula(XIII) with a compound of the above formula (XVII) and then reacting acompound of the above formula (XV) to obtain a compound represented bythe formula (XXV):

wherein R⁴, R⁶ and Z are as defined above, and

(2) a second step of reacting the compound of the above formula (XXV)obtained in the first step with a compound of the above formula (V) toobtain a nitroetheneamine derivative of the above formula (I′).

Each reaction in Process 12 can be carried out in the presence of asuitable solvent. The solvent to be specifically used may, for example,be an alcohol such as methanol, ethanol, propanol or butanol; anaromatic hydrocarbon such as benzene, toluene or xylene; an aliphatichydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroinor petroleum benzin; an ether such as diethyl ether, dipropyl ether,dibutyl ether, tetrahydrofuran or dioxane; a nitrile such asacetonitrile or propionitrile; an acid amide such as dimethylformamideor dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfonesuch as sulfolane; a phosphoric acid amide such ashexamethylphosphoramide; a halogenated hydrocarbon such as chloroform,dichloromethane, carbon tetrachloride or 1,2-dichloroethane; and asolvent mixture thereof.

In Process 12, in order to carry out each reaction efficiently, it ispreferred to carry out the reaction in the presence of a base. The baseto be specifically used may, for example, be an organic base such astriethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; an alkali metal carbonatesuch as lithium carbonate, sodium carbonate or potassium carbonate; analkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate or potassium hydrogencarbonate; an alkali metalhydride such as lithium hydride, sodium hydride or potassium hydride; oran alkoxide such as sodium methoxide, sodium ethoxide or potassiumt-butoxide. Further, in the second step of Process 12, the compound ofthe above formula (V) acts also as a base.

The reaction in the first step of Process 12 is carried out usually at areaction temperature of from −30 to 150° C, preferably at a reactiontemperature of from 0 to 80° C. The reaction time is usually from 0.1 to48 hours.

In the first step of Process 12, the compounds of the above formula(XVII) and the formula (XV) can be used in an amount of from 0.8 to 2equivalents, preferably from 1 to 1.5 equivalents, per mol of thecompound of the above formula (XIII), respectively.

The compound of the above formula (XXV) obtained in the first step ofProcess 12 may be supplied to the reaction of the second step of Process12 directly in the form of the reaction mixture or after separation andpurification by a known means such as concentration, concentration underreduced pressure, solvent extraction, recrystallization orchromatography.

The reaction of the second step of Process 12 is carried out usually ata reaction temperature of from −30 to 150° C., preferably at a reactiontemperature of from 0 to 80° C. The reaction time is usually from 0.1 to48 hours.

In the second step of Process 12, the compound of the above formula (V)can be used in an amount of from 1 to 1.5 equivalents per mol of thecompound of the above formula (XXV).

Various reaction conditions in Process 12 i.e. (1) the type and/or theamount of the compound of the formula (XIII), (2) the type and/or theamount of the compound of the formula (XVII), (3) the type and/or theamount of the compound of the formula (XV), (4) with or without use of asolvent in the reaction of the first step, (5) the type and/or theamount of the solvent in the reaction of the first step, (6) with awithout use of a base in the reaction of the first step, (7) the typeand/or the amount of the base in the reaction of the first step, (8) thereaction temperature of the first step, (9) the reaction time of thefirst step, (10) the type of the compound of the formula (XXV) which isan intermediate product in the first step, (11) with or withoutseparation and purification of the compound of the above formula (XXV),(12) the type and/or the amount of the compound of the formula (V), (13)with or without use of a solvent in the reaction of the second step,(14) the type and/or the amount of the solvent in the reaction of thesecond step, (15) with or without use of a base in the reaction of thesecond step, (16) the type and/or the amount of the base in the reactionof the second step, (17) the reaction temperature in the reaction of thesecond step, (18) the reaction time in the reaction of the second step,and (19) the type of the compound of the formula (I′) as the finaldesired product, may mutually suitably be combined. Further, among thesevarious reaction conditions, there are some which have a reactioncondition of a usual range and a reaction condition of a preferredrange, and they may also mutually suitably be selected and combined.

Combinations of the above various reaction conditions are also withinthe scope of Process 12.

The compounds of the above formula (I) (inclusive of compounds of theformula (I′), the formula (I″) and the formula (I′″)) obtained by theprocesses as described in the foregoing Processes 1 to 12, can beisolated and purified by a known means such as concentration,concentration under reduced pressure, distillation, fractionation,redistribution, solvent extraction, crystallization, recrystallizationor chromatography.

When the compound of the above formula (I) is obtained in a free form,it may be formed into a salt by a usual method. Further, the compound ofthe above formula (I) may form an intramolecular salt. The compounds ofthe above formula (I), and their stereoisomers or tautomer exhibitmatrix metalloproteinase inhibition activities individually or in astate of a mixture. The production flowcharts of the above-describedProcesses 1 to 12 will be shown below.

BEST MODE FOR CARRYING OUT THE INVENTION

Now, specific Preparation Examples for nitroetheneamine derivatives ofthe above formula (I) and the intermediates for their production, willbe described including specific embodiments of the processes for theproduction of nitroetheneamine derivatives represented by the aboveformula (I).

PREPARATION EXAMPLE 1 Preparation of 2-pyridinecarbaldehyde1-methylamino-2-nitroethenylhydrazone (Compound No. 29)

250 mg of N-methyl-1-hydrazino-2-nitroetheneamine, 210 mg of2-pyridinecarbaldehyde and 5 ml of ethanol were stirred for about 30minutes under heating and refluxing and then cooled to room temperature,whereupon precipitated crystals were collected by filtration. Thecrystals obtained by filtration were washed with a small amount ofethanol and then dried to obtain 300 mg of 2-pyridinecarbaldehyde1-methylamino-2-nitroethenylhydrazone (Compound No. 29) having a meltingof 165° C. (decomposed).

PREPARATION EXAMPLE 2 Preparation ofN-methyl-1-(2-methyl-2-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazino)-2-nitroetheneamine(Compound No. 35)

500 mg of N-methyl-1-methylthio-2-nitroetheneamine, 770 mg of1-methyl-1-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazine and 7 ml of1,4-dioxane were stirred for about 4 hours under heating and refluxingand then cooled to room temperature, and the solvent was distilled offunder reduced pressure. The concentrated residue was purified by silicagel column chromatography to obtain 370 mg ofN-methyl-1-(2-methyl-2-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazino)-2-nitroetheneamine(Compound No. 35) having a melting point of from 159 to 160° C.(decomposed).

PREPARATION EXAMPLE 3 Preparation ofN-methyl-1-(2-(4-trifluoromethyl-6-methoxy-2-pyridyl)hydrazino)-2-nitroetheneamine(Compound No. 98)

(1) 9 g of a 28% sodium methylate methanol solution was dissolved in 30ml of methanol, and a solution obtained by dissolving 10 g of2,6-dichloro-4-trifluoromethylpyridine in 15 ml of methanol, wasdropwise added thereto, followed by stirring for about 90 minutes underheating and refluxing. After completion of the reaction, the solutionwas cooled to room temperature, and about 40 ml of an ether was added,whereupon an insoluble substance was removed by filtration, and then thefiltrate was concentrated under reduced pressure. To the concentratedresidue, 15 ml of n-propanol and 6 g of hydrazine monohydrate wereadded, followed by stirring for about 19 hours under heating andrefluxing. After completion of the reaction, the solution was cooled toroom temperature, and the solvent was distilled off under reducedpressure. The concentrated residue was extracted with chloroform anddried over anhydrous sodium sulfate, whereupon the solvent was distilledoff under reduced pressure to obtain 6.6 g of crude4-trifluoromethyl-6-methoxy-2-pyridylhydrazine (Intermediate No. 71).

(2) 4.7 g of N-methyl-1-methylthio-2-nitroetheneamine, 6.6 g of crude4-trifluoromethyl-6-methoxy-2-pyridylhydrazine (Intermediate No. 71) and35 ml of ethanol were stirred for about 5.5 hours under heating andrefluxing and then cooled to room temperature, whereupon precipitatedcrystals were collected by filtration. The crystals obtained byfiltration were washed with a small amount of methanol and then dried toobtain 2.7 g ofN-methyl-1-(2-(4-trifluoromethyl-6-methoxy-2-pyridyl)hydrazino)-2-nitroetheneamine(Compound No. 98) having a melting point of 193° C. (decomposed).

PREPARATION EXAMPLE 4 Preparation ofN-(1-hydrazino-2-nitroethenyl)-4trifluoromethoxyaniline (Compound No.61)

(1) 3.00 g of 1,1-bis(methylthio)-2-nitroethene, 3.38 g of4-trifluoromethoxyaniline and 30 ml of ethanol were reacted for 5 hoursunder heating and refluxing and then cooled to room temperature,whereupon precipitated crystals were collected by filtration and washedwith a small amount of ethanol and dried to obtain 3.40 g of crystals,to which 1.81 g of 4-trifluoromethoxyaniline and 30 ml of ethanol wereadded and reacted for 6.5 hours under heating and refluxing. Aftercompletion of the reaction, the solution was cooled to room temperature,and precipitated crystals were collected by filtration, washed with asmall amount of ethanol and dried to obtain 2.51 g ofN-(1-methylthio-2-nitroethenyl)-4′trifluoromethoxyaniline (IntermediateNo. 30) having a melting point of from 114 to 115° C. (2) To 2.00 g ofN-(1-methylthio-2-nitroethenyl)-4-trifluoromethoxyaniline (IntermediateNo. 30) obtained in the above step (1), 40 ml of ethanol was added atroom temperature, and then 0.36 g of hydrazine monohydrate was dropwiseadded thereto. Thereafter, the reaction was carried out for 1 hour underheating and refluxing. After completion of the reaction, the solutionwas cooled to room temperature, and precipitated crystals were collectedby filtration, washed with a small amount of ethanol and dried to obtain1.36 g of the desired product (Compound No. 61) having a melting pointof 161° C. (decomposition point).

PREPARATION EXAMPLE 5 Preparation ofN-(1-(6-chloro-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide(Compound No. 157)

(1) In 20 ml of dimethylsulfoxide, 2.00 g ofN-((bismethylthio)methylene)methanesulfonamide, 0.92 g of nitromethaneand 2.27 g of potassium carbonate were added and reacted for 6 hours atroom temperature. The reaction mixture was poured into 75 ml of icewater and then acidified (pH=3) with 6N hydrochloric acid, whereuponprecipitated crystals were collected by filtration, washed with a smallamount of water and dried to obtain 0.49 g ofN-(1-(methylthio)-2-nitroethenyl)methanesulfonamide (Intermediate No.57) having a melting point of from 81 to 82° C.

(2) 0.40 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide(Intermediate No. 57) obtained in the above step (1), 0.40 g of6-chloro-4-trifluoromethyl-2-pyridylhydrazine and 10 ml of ethanol werestirred for 1.5 hours under heating and refluxing and then cooled toroom temperature, whereupon precipitated crystals were collected byfiltration. The crystals obtained by filtration were washed with a smallamount of ethanol and then dried to obtain 0.37 g ofN-(1-(6-chloro-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide(Compound No. 157) having a melting point of 190° C. (decomposed).

PREPARATION EXAMPLE 6 Preparation ofN-(1-(6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide(Compound No. 164)

1.40 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide(Intermediate No. 57), 1.80 g of6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridylhydrazine and 11 ml ofethanol were stirred for 15 hours under heating and refluxing and thencooled to room temperature, whereupon precipitated crystals werecollected by filtration. The crystals obtained by filtration were washedwith a small amount of ethanol and then dried to obtain 0.97 g ofN-(1-(6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide(Compound No. 164) having a melting point of 153° C.

PREPARATION EXAMPLE 7 Preparation ofN-(1-(N-morpholino)amino-2-nitroethenyl)methanesulfonamide (Compound No.163)

(1) 0.32 ml of nitromethane, 0.24 g of sodium hydride and 20 ml ofN,N-dimethylformamide were stirred for 1 hour in a nitrogen atmosphere,and then 1.57 g of N-((bismethylthio)methylene)benzenesulfonamide wasadded thereto and reacted for 22 hours at room temperature. The reactionmixture was poured into 200 ml of ice water, and n-hexane was added andstirred for 30 minutes, followed by liquid separation to remove anorganic layer. The aqueous layer was acidified (pH=3) with 6Nhydrochloric acid, and then the oil content was extracted with an ether.The obtained extract solution was washed with water and with a saturatedsodium chloride aqueous solution and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtain1.27 g of oily N-(1-(methylthio)-2-nitroethenyl)benzenesulfonamide(Intermediate No. 56).

(2) 0.27 g of N-(1-(methylthio)-2-nitroethenyl)benzenesulfonamide(Intermediate No. 56) obtained in the above step (1), 0.10 g ofN-aminomorpholine and 4 ml of ethanol were stirred for 24 hours underheating and refluxing and then cooled to room temperature, whereuponprecipitated crystals were collected by filtration. The crystalsobtained by filtration were washed with a small amount ofethanol/n-hexane mixed liquid (1/1) and then dried to obtain 0.22 g ofN-(1-(N-morpholino)amino-2-nitroethenyl)methanesulfonamide (Compound No.163) having a melting point of from 127 to 130° C.

Preparation Examples of compounds of the above formula (I) prepared bythe methods of Preparation Examples 1 to 7 and in accordance with theabove-described Processes 1 to 12, are shown in the following Tables 1to 23.

TABLE 1

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 1 H —CH₂Ph H CH₃ H Hmp 151° C. (decom- posed) 2 H -Ph H -Ph H H mp 155° C. (decom- posed) 3H —COPh H CH₃ H H mp 163° C. (decom- posed) 4 H —COCH₃ H CH₃ H H mp 164°C. (decom- posed) 5 H —COOPh H CH₃ H H mp 159° C. (decom- posed) 6 H—COOCH₃ H CH₃ H H mp 147° C. (decom- posed) 7 H -Bu(t) H CH₃ H H mp 178°C. (decom- posed) 8 H

H CH₃ H H mp 178° C. (decom- posed) 9 H

H CH₃ H H mp 191° C. (decom- posed) 10  H

H CH₃ H H mp 187° C. (decom- posed) 11  H

H CH₃ H H mp 194° C. (decom- posed)

TABLE 2

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 12 H

H CH₃ H H mp 176° C. (decom- posed) 13 H

H CH₃ H H mp 186° C. (decom- posed) 14 H

H CH₃ H H mp 171° C. (decom- posed) 15 H

H CH₃ H H mp 189° C. (decom- posed) 16 H

H CH₃ H H mp 186° C. (decom- posed) 17 H

H CH₃ H H mp 168° C. (decom- posed) 18 H

CH₃ H H mp 169- 170° C. 19 H

H CH₃ H H mp 207° C. (decom- posed) 20 H

CH₃ H H mp 134° C. 21 H

H CH₃ H H mp 168° C. (decom- posed) 22 H

H CH₃ H H mp 156° C. (decom- posed)

TABLE 3

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 23 H

H CH₃ H H mp 144- 145° C. 24 H

CH₃ H H mp 224° C. (decom- posed) 25 H

CH₃ H H mp 136° C. 26 H

CH₃ H H mp 159° C. (decom- posed) 27 H

H CH₃ H H mp 161- 162° C. 28 H

CH₃ H H mp 196° C. (decom- posed) 29 H

CH₃ H H mp 165° C. (decom- posed) 30 H

H CH₃ H H mp 164° C. (decom- posed) 31 H

CH₃ H H mp 202° C. (decom- posed)

TABLE 4

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 32 H

CH₃ H H mp 165° C. (decom- posed) 33 H

CH₃ H H mp 170° C. (decom- posed) 34 H

CH₃ H H mp 181° C. (decom- posed) 35 H

CH₃ CH₃ H H mp 159- 160° C. 36 H

CH₃ CH₃ H H mp 153- 154° C. 37 H

H CH₃ H H mp 215- 217° C. (decom- posed) 38 H

CH₃ H H mp 199° C. (decom- posed) 39 H

CH₃ CH₃ H H mp 191- 192° C. (decom- posed) 40 H

H CH₃ H H mp 190° C.

TABLE 5

Comp. No. R¹ R² R³ R⁴ R⁵ R⁶ Physical property 41 H

H

H H mp 155-157° C. 42 H

H CH₃ H H md 250° C.< 43 H

H

H H mp 130-135° C. 44 H

H CH₃ H H mp 192-193° C. (decomposed) 45 H

H CH₃ H H mp 182-183° C. (decomposed) 46 H H H CH₃(CH₂)₇— H H mp106-108° C. 47 H H H CH₃(CH₂)₉— H H mp 109-110° C. 48 H H H

H H mp 191° C. (decomposed) 49 H H H

H H mp 195° C. (decomposed) 50 H H H

H H mp 175° C. (decomposed) 51 H H H

H H mp 188° C. (decomposed)

TABLE 6

Comp. No. R¹ R² R³ R⁴ R⁵ R⁶ Physical property 52 H H H

H H mp 144° C. 53 H H H

H H mp 183.5° C. (decomposed) 54 H H H

H H mp 180° C. (decomposed) 55 H H H

H H mp 176° C. (decomposed) 56 H H H

H H mp 148° C. 57 H H H

H H mp 135.5-136° C. 58 H H H

H H mp 177° C. (decomposed) 59 H H H

H H mp 180° C. (decomposed) 60 H H H

H H mp 130° C. 61 H H H

H H mp 161° C. (decomposed) 62 H H H —CH₂CH₂OCH₃ H H mp 81-83° C. 63 H HH —(CH₂)₃OC₂H₅ H H Oily

TABLE 7

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 64 H H H

H H mp 148° C. (decomposed) 65 H H H

H mp 142° C. (decomposed) 66 H H H —NH₂ H H mp 154° C. (decomposed) 67 HH H

H H mp 187° C. (decomposed) 68 H H H

H H mp 179° C. (decomposed) 69 H H H

H H mp 160° C. (decomposed) 70 H H H

H H mp 198° C. (decomposed) 71 H H H

H H mp 179° C. (decomposed) 72 H H H

H H mp 177° C. (decomposed) 73 H H H

H H mp 68-70° C. 74 H H H

H H mp 155° C. (decomposed) 75 H H H

H H mp 206° C. (decomposed)

TABLE 8

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 76 H H H

H H mp 190° C. (decomposed) 77 H H H

H H mp 155° C. 78 H H H

H H mp 162° C. 79 H H H

H H mp 190° C. (decomposed) 80 H H H

H H mp 203° C. (decomposed) 81 H H H

H H mp 160-161° C. 82 H CH₃ H CH₃ H H mp 130° C. (decomposed) 83 H CH₃CH₃ CH₃ H H mp 135-139° C. 84 H H Ph CH₃ H H mp 178° C. (decomposed) 85H H H -Bu(n) H H mp 118-120.5° C. 86 H H H

H H mp 196° C. (decomposed) 87 H H H

H H mp 153° C. (decomposed)

TABLE 9

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 88 H H H —CH(CH₃)₂ H Hmp 172° C. (decomposed) 89 H H H -Pr(n) H H mp 104-106° C. 90 H H H

H H mp 145° C. (decomposed) 91 H H H

H H mp 192° C. (decomposed) 92 H H H

H H mp 140-143° C. 93 H H H CH₃ H H mp 190° C. (decomposed) 94 H

H CH₃ H H mp 174-175° C. (decomposed) 95 H

H CH₃ H H mp 176-177° C. (decomposed) 96 H

H CH₃ H H mp 165-167° C. (decomposed) 97 H

H CH₃ H H mp 217˜218° C. (decomposed) 98 H

H CH₃ H H mp 193° C. (decomposed)

TABLE 10

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property  99 H

H CH₃ H H mp 180-181° C. (decomposed) 100 H

H CH₃ H H mp 125-126° C. (decomposed) 101 H

H CH₃ H H mp 160-162° C. (decomposed) 102 H

H CH₂CH₃ H H mp 206° C. (decomposed) 103 H

H H H H mp 201-202° C. (decomposed) 104 H

H CH₃ H H mp 202-203° C. (decomposed) 105 H

H CH₃ H H mp 166-167° C. (decomposed) 106 H

H CH₃ H H mp 185-186° C. (decomposed) 107 H

H CH₃ H H mp 167-168° C. (decomposed) 108 H —SO₂CH₃ H CH₃ H H mp167-168° C. (decomposed) 109 H

H CH₃ H H mp 169-170° C. (decomposed)

TABLE 11

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 110 H H H

H H mp 177-180° C. (decomposed) 111 H H H

H H mp 210-214° C. (decomposed) 112 H H H

H H mp 193-197° C. (decomposed) 113 H H H

H H mp 196-199° C. (decomposed) 114 H H H

H H mp 212.5° C. 115 H H H

H H mp 162-165° C. 116 H H H

H H mp 180-183° C. 117 H H H —CH₂CH₃ H H mp 93.5-98.5° C. 118 H

H CH₃ H H mp 169° C. (decomposed) 119 H

H CH₃ H H mp 149° C. (decomposed) 120 H

H CH₃ H H mp 154° C. (decomposed)

TABLE 12

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 121 H

H CH₃ H H mp 176° C. (decomposed) 122 H

H CH₃ H H mp 170° C. (decomposed) 123 H

H CH₃ H H mp 131° C. (decomposed) 124 H

H CH₃ H H mp 181° C. (decomposed) 125 H

H CH₃ H H mp 192° C. (decomposed) 126 H

H CH₃ H H mp 141° C. (decomposed) 127 H

H CH₃ H H mp 202 C. (decomposed) 128 H

H CH₃ H H mp 93-95° C. 129 H

H CH₃ H H mp 97-99° C. 130 H

H CH₃ H H mp 175° C. (decomposed) 131 H

H CH₃ H H mp 165° C. (decomposed)

TABLE 13

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 132 H

H CH₃ H H mp 158° C. (decomposed) 133 H

H CH₃ H H mp 209° C. (decomposed) 134 H

CH₃ H H mp 186° C. (decomposed) 135 H

CH₃ H H mp 190° C. (decomposed) 136 H

CH₃ H H mp 186° C. (decomposed) 137 H

CH₃ H H mp 172° C. (decomposed) 138 H

CH₃ H H mp 232° C. (decomposed) 139 H

CH₃ H H mp 187° C. (decomposed) 140 H

CH₃ H H mp 180° C. (decomposed) 141 H

CH₃ H H mp 179° C. (decomposed) 142 H

CH₃ H H mp 210° C. (decomposed)

TABLE 14

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 143 H

CH₃ H H mp 173° C. (decomposed) 144 H

CH₃ H H mp 180° C. (decomposed) 145 H

H CH₃ H H mp 221° C. (decomposed) 146 H

H CH₃ H H mp 210° C. (decomposed) 147 H

H CH₃ H H mp 235° C. (decomposed) 148 H

H CH₃ H H mp 272° C. (decomposed) 149 H

H CH₃ H H mp 145° C. (decomposed) 150 H

H CH₃ H H mp 168° C. (decomposed) 151 H

H CH₃ H H mp 129-130° C. 152 H H H

H H mp 209-213° C. (decomposed) 153 H

H

H H mp 128-130° C.

TABLE 15 Comp. Physical No. Compound of the general formula (I) property154

mp 126-127° C. 155

mp 168-170° C. (decomposed)

TABLE 16

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 156 H H H

H H mp 210° C. (decomposed) 157 H

H —SO₂CH₃ H H mp 190° C. (decomposed) 158 H

H CH₃ H H mp 220-223° C. 159 H

H

H H mp 170-173° C. (decomposed) 160 H

H —CH₂CH₂OCH₃ H H mp 175-178° C. (decomposed)

TABLE 17

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 161 H

H —SO₂CH₂CH₃ H H mp 114-119° C. (decomposed) 162 H

H

H H mp 171-174° C. 163 H

H H mp 127‥130° C. 164 H

H —SO₂CH₃ H H mp 153° C. 165 H

H —SO₂CH₃ H CH₃ mp 30-33° C. 166 H

CH₃ H H mp 188-189° C. 167 H

CH₃ H H mp 180° C. 168 H

H CH₃ H H mp 197° C. (decomposed) 169 H

H

H H mp 164° C. (decomposed) 170 H

H CH₃ H H mp 216° C. (decomposed) 171 H

H CH₃ H H mp 188° C. (decomposed)

TABLE 18

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 172 H

H CH₃ H H mp 206° C. (decomposed) 173 H

H CH₃ H H mp 160° C. (decomposed) 174 H

H CH₃ H H mp 162° C. (decomposed) 175 H

H CH₃ H H mp 157° C. (decomposed) 176 H

H CH₃ H H mp 146° C. 177 H

H CH₃ H H mp 169° C. (decomposed) 178 H

H CH₃ H H mp 161° C. (decomposed) 179 H

CH₃ H H mp 171° C. (decomposed) 180 H

H CH₃ H H mp 160° C. (decomposed) 181 H

H CH₃ H H mp 180° C. (decomposed) 182 H

H CH₃ H H mp 138° C.

TABLE 19

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 183 H

H CH₃ H H mp 135° C. 184 H

H CH₃ H H mp 167° C. (decomposed) 185 H

H CH₃ H H mp 167° C. (decomposed) 186 H

H CH₃ H H mp 197° C. (decomposed) 187 H

H CH₃ H H mp 195° C. (decomposed) 188 H

H CH₃ H H mp 166° C. (decomposed) 189 H

H CH₃ H H mp 94° C. 190 H

H CH₂CH₂N(CH₃)₂ H H mp 90° C. 191 Hydrochloride of Compound No. 190 mp201° C. (decomposed) 192 H

H CH₃ H H mp 128° C. 193 H

H CH₃ H H mp 170° C. (decomposed) 194 H

H CH₃ H H mp 128° C.

TABLE 20

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 195 H

H CH₃ H H mp 170° C. (decomposed) 196 H

H CH₃ H H mp 167° C. (decomposed) 197 H

H CH₃ H H mp 147° C. 198 H

H —(CH₂)₃OH H H mp 134-135° C. 199 H

H —(CH₂)₄OH H H mp 150-151° C. 200 H

H

H H mp 144-145° C. 201 H

H —SO₂CH₃ H H mp 191-193° C. 202 H

H —SO₂CH₃ H H mp 170° C. (decomposed) 203 H

H —SO₂CH₃ H H mp 62-68° C. 204 H

H

H H mp 200° C. (decomposed) 205 H

H CH₃ H H mp 208° C. (decomposed)

TABLE 21

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 206 H

H —SO₂CH₃ H H 207 H

H

H H mp 206° C. (decomposed) 208 H

H —SO₂CH₃ H H mp 92-93° C. 209 H

—SO₂CH₃ H H mp 188° C. (decomposed) 210 H

H H mp 163° C. 211 H

—SO₂CH₃ H H mp 236° C. (decomposed) 212 H

H H mp 172° C. 213 H

—CH₂CH(CH₃)₂ H H 214 H

—CH(CH₃)₂ H H 215 H

—SO₂CH₃ H H mp 140-142° C. 216 H

—SO₂C₂H₅ H H 217 H

H H

TABLE 22

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 218 H

H —SO₂CH₃ H H 219 H

H —SO₂CH₃ H H 220 H

H —SO₂CH₃ H H 221 H

H —SO₂CH₃ H H 222 H

H —SO₂CH₃ H H 223 H

H —SO₂CH₃ H H 224 H

H —SO₂CH₃ H H 225 H

H —SO₂CH₃ H H 226 H

H —SO₂CH₃ H H 227 H

H —SO₂CH₃ H H 228 H

H —SO₂CH₃ H H

TABLE 23

(I) Comp. Physical No. R¹ R² R³ R⁴ R⁵ R⁶ property 229 H

H

H H 230 H

H —SO₂CH₃ H H 231 H

H —SO₂CH₃ H H 232 H

H —SO₂CH₃ H H 233 H

H —SO₂CH₃ H H 234 H

H —SO₂CH₃ H H 235 H H H —SO₂CH₃ H H Oily 236 H

H H mp 160-162° C. (decomposed)

Preparation Examples of compounds of the above formula (IV) which areintermediates for the preparation of compounds of the above formula (I)prepared by a process in accordance with the above-described Process1-1, are shown in the following Tables 24 to 29.

TABLE 24

(IV) Inter- mediate Physical No. Z R⁴ R⁵ R⁶ property 1 CH₃ —CH₂CH₂CH₃ HH mp 63-64° C. 2 CH₃

H H mp 101.5-106° C. 3 CH₃

H H mp 82-87.5° C. 4 CH₃

H H mp 101-112° C. 5 CH₃ —CH₃ H H mp 111.5-114.5° C. 6 CH₃ —CH₂CH₃ H Hmp 65-66.5° C. 7 CH₃ —CH₂CH₂CH₂CH₃ H H mp 50-51° C. 8 CH₃

H H mp 105-107° C. 9 CH₃ -Ph H H mp 140.5-149° C. 10  CH₃ —CH(CH₃)₂ H Hmp 94-97.5° C. 11  CH₃

H H mp 180° C.

TABLE 25

(IV) Inter- mediate Physical No. Z R⁴ R⁵ R⁶ property 12 CH₃

H H mp 193° C. (decomposed) 13 CH₃

H H mp 94-95° C. 14 CH₃ —(CH₂)₇CH₃ H H mp 36-38° C. 15 CH₃ —(CH₂)₉CH₃ HH mp 42.5-45° C. 16 CH₃

H H mp 140-142° C. 17 CH₃

H H mp 138-141° C. 18 CH₃

H H mp 159-160° C. 19 CH₃

H H mp 152-155° C. 20 CH₃

H H mp 118-121° C. 21 CH₃

H H mp 156° C. 22 CH₃

H H mp 131-132° C. 23 CH₃

H H mp 99-101° C.

TABLE 26

Intermediate No. Z R⁴ R⁵ R⁶ Physical Property 24 CH₃

H H mp 159.5-160° C. 25 CH₃

H H mp 128-130° C. 26 CH₃ —CH₂COOCH₂CH₃ H H mp 79-81° C. 27 CH₃

H H mp 89-91° C. 28 CH₃

H H mp 75-76° C. 29 CH₃

H H mp 97.5-98.5° C. 30 CH₃

H H mp 114-116° C. 31 CH₃ —CH₂CH₂OCH₃ H H mp 96-97° C. 32 CH₃—(CH₂)₃OCH₂CH₃ H H Oily 33 CH₃

H H mp 117-119° C. 34 CH₃

H mp 63-68° C. 35 CH₃

H mp 38-42° C.

TABLE 27

(IV) Inter- mediate Physical No. Z R⁴ R⁵ R⁶ property 36 CH₃

H H mp 174-175° C. 37 CH₃

H H mp 140-141° C. 38 CH₃

H H mp 142-143° C. 39 CH₃

H H mp 164-165° C. 40 CH₃

H H mp 155-155.5° C. 41 CH₃

H H mp 156.5-157° C. 42 CH₃

H H mp 105-106° C. 43 CH₃

H H mp 139-140° C. 44 CH₃

H H mp 144° C. (decomposed) 45 CH₃

H H mp 157-158° C. 46 CH₃

H H mp 135-137° C.

TABLE 28

(IV) Inter- mediate Physical No. Z R⁴ R⁵ R⁶ property 47 CH₃

H H mp 169- 172° C. 48 CH₃

H H mp 204- 206° C. (decom- posed) 49 CH₃

H H mp 134- 137° C. 50 CH₃

H H mp 116- 123° C. 51 CH₃

H H mp 153- 155° C. 52 CH₃

H H mp 221- 222° C. (decom- posed) 53 CH₃

H H mp 196- 197° C. 54 CH₃

H H mp 184- 188° C. 55 CH₃

H H mp 214- 216° C. 56 CH₃ —SO₂Ph H H Oily 57 CH₃ —SO₂CH₃ H H mp 81-82°C.

TABLE 29

(IV) Inter- mediate Physical No. Z R⁴ R⁵ R⁶ property 58 CH₃

H H 59 CH₃ —SO₂CH₂CH₃ H H Oily 60 CH₃

H H mp 189-191° C. (decomposed) 61 CH₃

H H mp 205° C. (decomposed) 62 CH₃

H H mp 75-77° C. 63 CH₃ —OCH₃ H H nD 1.5150 (30° C.) 64 CH₃ —SO₂CH₃ H HnD 1.5150 (30° C.) 65 CH₃ —SO₂CH₃ H H nD 1.5286 66 CH₃

H H Oily 67 CH₃ —CH₂CH₂N(CH₃)₂ H H 68 CH₃ —CH₂CH₂CH₂OH H H 69 CH₃—CH₂CH₂CH₂CH₂OH H H 70 CH₃ —CH₂CH(CH₃)₂ H H mp 52-54° C.

Among the compounds of the above formula (V) as intermediates to be usedfor the above Processes 1, 2 and 4, compounds represented by the formula(V′):

wherein R is as defined below, which are compounds wherein Y, R¹ and R³is a hydrogen atom, and R² is:

wherein R is a halogen atom (provided that a chlorine atom is excluded)or an organic group (provided that a trifluoromethyl group, a methylgroup, a phenyl group and a thienyl group are excluded), are novelcompounds and can be prepared by a method in accordance with abovePreparation Example 3(1). Specific Preparation Examples thereof areshown in Tables 30 to 33.

TABLE 30

(V′) Intermediate No. R Physical property 71 CH₃O— mp 52-53° C. 72CH₃CH₂O— mp 72-76° C.

TABLE 31

(V′) Intermediate No. R Physical property 73

Oily 74 CH₃CH₂OCH₂CH₂O— mp 48-49° C. 75 (CH₃)₂N—CH₂CH₂O— mp 96-97° C. 76CH₃S— mp 102-103° C. 77

mp 55-58° C. 78

mp 59-60° C. 79

Oily 80

mp 77-80° C. 81

mp 70-73° C. 82

mp 118-119° C. 83

mp 98-100° C. 84

mp 79-81° C.

TABLE 32

(V′) Intermediate No. R Physical property 85

mp 96-97° C. 86 —OCH═CH₂ Oily 87

mp 33-34° C. 88

mp 123° C. 89

mp 86-87° C. 90

mp 51-55° C. 91 —OCH₂CH₂CH₃ mp 51-52° C. 92 —OCH₂CH₂CH₂CH₃ mp 33-35° C.93

mp 40-42° C. 94 —OCH₂CF₃ mp 71-72° C. 95 —OCH₂CH₂OCH₃ mp 39-40° C. 96

oily 97

mp 63-64° C.

TABLE 33

(V′) Intermediate No. R Physical property  98

mp 72-73° C.  99

mp 64-66° C. 100 —OCH₂CH₂SCH₃ mp 55-56° C. 101 —OCH₂CH₂OCH₂CH₂CH₂CH₃Oily 102 —OCH₂CH₂OC(CH₃)₃ mp 100-101° C. 103 —OCH₂CH₂OCH₂CH₂OCH₃ Oily104

mp 44-45° C. 105 —OCH₂CH₂OCH(CH₃)₂ mp 62-63° C. 106 —OCH₂CH₂CH₂OCH₂CH₃Oily

Nitroetheneamine derivatives represented by the formula (I) or saltsthereof have matrix metalloproteinase inhibition activities,particularly MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9 inhibition activities.Among them, MMP-3- and MMP-9 inhibition activities are particularlyexcellent, and MMP-9 inhibition activities are the best. Not only thecompounds of the above formula (I) and salts thereof, compounds of theabove formula (IV) or salts thereof, which are intermediates for thepreparation of the compounds of the above formula (I) have theabove-described matrix metalloproteinase inhibition activities.Accordingly, by using them as active constituents and by combining theafter-mentioned carrier, etc., as the case requires, matrixmetalloproteinase inhibitors of the present invention can be provided.Further, a medical composition will be provided which comprises atherapeutically effective amount of the compound of the above formula(I) or a salt thereof, or the compound of the above formula (IV) or asalt thereof and a pharmaceutically acceptable carrier. To apply thepharmaceutical composition of the present invention to clinicaltreatment as an angiogenesis inhibitor, an anticancer agent, a tumorcell infiltration inhibitor or a tumor metastatis inhibitor to be usedfor treatment or prevention of a cancer or inflammatory diseases or as atherapeutic or preventive agent for rheumatoid arthritis, it ispreferred to make it a formulation having an additive such as a diluent,an excipient or a stabilizer further incorporated as the case requiresto the medical composition comprising the above active constituent andthe pharmaceutical acceptable carrier.

In the medical composition of the present invention, the blendproportion of the above active constituent to the carrier component isusually from 1.0 to 90% w/w. The dosage effective for treatment isusually from 0.1 to 1000 mg/day/person in the case of an adult, althoughit varies depending upon e.g. the administration method, the sex, theweight and the age of the patient and the disease to be treated.

With respect to the formulation and the administration mode, it may beorally administered in the form of a formulation such as a granule, aloose granule or a pilula, a tablet, a capsule or a solution or in theform of a bulk powder, or it may be administered by non-oral route inthe form of a suppository, an aerosol or formulation for localadministration such as collunarium. As an injection solution, it may beadministered by intravenous administration, intramuscularadministration, subcutaneous administration or articular cavityadministration. Further, it may be prepared in the form of a powder forinjection and may be formulated at the time of use.

A pharmaceutical, organic or inorganic, solid or liquid carrier ordiluent suitable for oral, enteral or perenteral administration can beused for formulating the medical composition of the present invention. Atypical carrier or diluent which can be incorporated to tablets orcapsules, may be a disintegrant such as Acacia, corn starch or alginicacid, a lubricant such as magnesium stearate or a sweetener such assaccharose or lactose. When the formulation is capsules, in addition tothe above substance, a liquid carrier such as fatty oil may beincorporated. Various other substances can be used as a coating agent ora physical shape improving agent for a dosage unit. For example, it ispreferred to dissolve or suspend the active ingredient in water or in anexcipient such as natural vegetable oil or in a synthetic fattyexcipient such as ethyl oleate. A buffer agent such as a citrate, anacetate or a phosphate, or an anti oxidant such as ascorbic acid, mayalso be incorporated in accordance with an acceptable medical method.

Test Examples

Now, specific Test Examples will be described wherein MMP inhibitionactivities of nitroetheneamine derivatives represented by the aboveformula (I) were measured.

Test Example 1 Measurement of the Enzyme Inhibition Activity AgainstMMP-3 (Stromelysin-1)

The inhibition activity against human MMP-3 was measured using afluorescent peptide substrateMOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH₂ [NFF-3,manufactured by Peptide Institute, Inc. (No. 3168-v)] with reference tothe method disclosed in a literature (Knight C. G. et al, FEBS Letters,Vol. 296, 263-266, 1992, Nagase H. et al, Journal of BiologicalChemistry, Vol. 269, 20952-20957, 1994). Namely, into each well of aFluoro Nunc plate (96C) white (No. 437842, manufactured by Nunc Co.),180 μl of a MMP-3 solution (0.0125 unit/ml; No. YU-26003, manufacturedby Kabushiki Kaisha Yagai Chuo Kenkyusho, purity: at least 99%), 10 μlof a test materials (the compound of the present invention) dissolved inDMSO and 10 μl of a peptide substrate enzyme (final concentration: 10μM) were added and maintained at 37° C. for 2 hours in a dark place.Dilution of the enzyme was carried out by using 50 mM of Tris-HCl (pH7.5) comprising 0.1M of NaCl, 10 mM of CaCl₂, 0.05% Brij 35 and 0.02% ofNaN₃.

For the MMP-3 enzymatic activity, the amount of the decompositionproduct after the reaction was quantitatively analyzed as the change inthe relative fluorescence intensity at a fluorescence wavelength of 400nm with an excitation wavelength of 326 nm (using a variablefluorescence plate reader (variable wavelength type) Spectron FL-2575,manufactured by Towa Kagaku K.K.), and the inhibition activity of thetest materials against the enzymatic activity was calculated bycomparing the relative fluorescence intensities of the inhibitor addedgroup and the non-added group after completion of the reaction. The testresults are shown in Table 34.

TABLE 34 Inhibition activity against MMP-3 IC₅₀(μmol/1) Compound No. 157Compound No. 107 Compound No. 164 IC₅₀ 24.2 22.3 17.8

Test Example 2 Measurement of the Enzyme Inhibition Activity AgainstMMP-7 (Matrilysin)

The inhibition activity against human MMP-7 was measured by the samemethod as the method for MMP-3, by using a MMP-7 solution (0.025unit/ml; No. YU-31001, manufactured by Kabushiki Kaisha Yagai ChuoKenkyusho, purity: at least 99.9%) and a fluorescent peptide substrateMOCAc-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH₂ [NFF-2, No.3167-v, manufactured by Peptide Institute, Inc.]. The enzymatic reactionwas carried out at 37° C. for 2.5 hours in a dark place, and therelative fluorescence intensity was measured at a fluorescencewavelength of 400 nm with an excitation wavelength of 327 nm. The testresults are shown in Table 35.

TABLE 35 Inhibition activity against MMP-7 IC₅₀(μmol/1) CompoundCompound Compound Compound No. No. 37 No. 157 No. 107 164 IC₅₀ 24.5 16.518.7 12.0

Test Example 3 Measurement of the Inhibition Activity of the Compound ofthe Formula (I) Against Human MMP-9 (Gelatinase B)

(1) Preparation of Human MMP-9

Human MMP-9 (gelatinase B) was purified by the following method from aculture supernatant of HT1080 cells (human fibrosarcoma).

(1-1) Preparation of a Crude Enzyme Solution

2.5×10⁶ HT1080 cells (ATCC CCL-121, purchased from Dainippon Seiyaku)were inoculated to a tissue culture dish (Code No. 3020-100,manufactured by Iwaki Glass Co., Ltd.) having a diameter of 10 cm andcontaining 10 ml of Dulbecco's Modified Eagle Medium (DME, No. D-5648,manufactured by Sigma Co.) containing 10% fetal bovine serum (FBS:REHATUIN™, Code No. 1020-90, manufactured by Intergen Co.) and culturedfor 72 hours at 37° C. in an atmosphere comprising 5% of CO₂ and 95% ofair (Carbon Dioxide Incubator LNA-122D Model, manufactured by TabaiCo.). Then, the medium was changed to 10 ml of a DME culture mediumcontaining no FBS, and phorbol 12-myristate 13-acetate (PMA, code No.163-114851, manufactured by Wako Pure Chemical Industries, Ltd.) wasadded so that the final concentration became 10 ng/ml. Under the sameconditions, the culturing was carried out for further 20 hours,whereupon the culture supernatant was collected and subjected to coolcentrifugation at 4° C. for 5 minutes (cool centrifugal separator,manufactured by Hitachi) to remove cell fragments.

(1-2) Column Separation

The pH of a conditioned medium (50 ml) containing MMP-9, thus prepared,was adjusted to 8.0 with 0.2N NaOH. Then, purification was sequentiallycarried out by the following column operation by a partially improvedmethod by Tanzawa et al (Journal of Antibiotics, Vol. 45, 1733, 1992).Namely, the above-mentioned conditioned medium was passed throughDEAE-Sephacel (manufactured by Pharmacia, gel volume: about 35 ml)preliminarily equilibrated with 50 mM Tris-HCl, pH 8.0 (A buffer), and anon-adsorption fraction was collected. Then, it was added to Dye MatrixGel Green A (manufactured by Amicon Co., gel volume: about 6 ml)preliminarily equilibrated with 50 mM Tris-HCl, pH 7.5/10 mM CaCl₂/0.05%Brij 35/0.02% NaN₃ (B buffer) and thoroughly washed with the samebuffer, whereupon the adsorbed enzyme was eluted with a 1MNaCl-containing B buffer. About 7.5 ml of the eluted fraction wasdiluted twice with the B buffer and added to Gelatin-Sepharose 4B(manufactured by Pharmacia, gel volume: about 6 ml) preliminarilyequilibrated with a 0.5 M NaCl-containing B buffer. It was thoroughlywashed with a 0.5M NaCl-containing B buffer, and eluted with the Bbuffer containing 10% of dimethylsulfoxide (DMSO) and 0.5 M of NaCl. 5.5ml of the eluted fraction was dialyzed against a 0.1 M NaCl-containing Bbuffer to obtain 5.2 ml of a purified enzyme solution. The purifiedMMP-9 standard product was confirmed to have a single band of 92 kDa bya protein staining by SDS electrophoresis, and further, it was confirmedto have an adequate gelatin decomposing activity by gelatinzymography(carried out in accordance with a method by Howard E. W. et al; JournalBiological Chemistry, Vol. 266, 13064-13069, 1991) and to have anadequate substrate decomposing activity by the after-mentionedmeasurement employing a fluorescent peptide substrate specific to MMP.

(2) Measurement of the Inhibitory Activity Against Human MMP-9(Gelatinase B)

The inhibition activity against human MMP-9 was measured by thefollowing method in accordance with the method by C. G. Knight et al(FEBS Letters, Vol, 296, 263-266, 1992) employing a fluorescent peptidesubstrate(7-methoxycoumarin-4-yl)Acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-Ala-Arg-NH₂,Code 3163-VC, manufactured by Peptide Institute, Inc.

Further, as the case requires, commercially available human MMP-9purified enzyme (No. YU-18003, manufactured by Kabushiki Kaisha YagaiChuo Kenkyusho; used in a final concentration of from 0.0125 to 0.025unit/ml, No. CC079, manufactured by Chemicon International, Inc.; usedin a final concentration of 0.2 μg/ml) was used for the tests.

Into a micro-centrifuging tube having a capacity of 1.5 ml, 380 μl ofthe MMP-9 solution (in the case of commercially available purifiedenzyme, it was used in a final concentration of from 0.0125 to 0.025unit/ml or 0.2 μg/ml), 10 μl of compound No. 2, 8, 9, 10-30, 32-46,48-57, 60-61, 67, 70-74, 76-79, 82-88, 90-112, 115, 117, 118-120,122-132, 135-138, 140-142, 144-148, 152-153, 155-157, 159-170, 172, 174,177-179, 181-182, 184, 186, 188-189, 191-197, 199 and 202 andIntermediate No. 1-3, 5-7, 10-12, 16, 19-21, 24, 25, 47, 49-52, 54, 55,57, 59 and 61-64) dissolved in DMSO, and 10 μl of 400 μM fluorescentpeptide substrate dissolved in DMSO (final concentration: 10 μM) wereadded and maintained at 37° C. for 3 hours in a dark place. MMP-9 waspresent in the form of an inert precursor, and accordingly, 10 μl of a38 mM 4-aminophenylmercuric acetate (APMA, Code No. A0395, manufacturedby Tokyo Kasei) (final concentration: 1 mM) was preliminarily added to370 μl of the enzyme solution, and the mixture was left to stand at 4°C. for 20 hours to convert it to an active form, whereupon it wassupplied to the test for the enzyme inhibition activity. Further,dilution of the enzyme was carried out by means of 50 mM Tris-HCl (pH7.5) comprising 0.1 M of NaCl, 10 mM of CaCl₂, 0.05% of Brij 35 and0.02% NaN₃.

For the MMP-9 activity, the amount of the decomposition product afterthe reaction was quantitatively analyzed as a change in the relativefluorescence intensity at a fluorescent wavelength of 393 nm with anexcitation wavelength of 328 nm (using F4000 model fluorescentspectrophotometer, manufactured by Hitachi, Ltd., and the inhibitionactivity by the test materials against the enzyme activity wascalculated by comparing the relative fluorescence intensities of theinhibitor-added group and the non-added group after completion of thereaction.

Further, when the enzymatic reaction was carried out by means of amicroplate (Fluoro Nunc Plate (96C) White (No. 437842, manufactured byNunc Co.)), a variable fluorescence plate reader (variable wavelengthtype) (Spectron FL-2575 (manufactured by Towa Kagaku K.K.) was used, andthe measurement was carried out at a fluorescence wavelength of 400 nmwith an excitation wavelength of 327 nm.

The measurement of the MMP-9 inhibition activity in Test Example 3 wascarried out once or twice for each, and the results are shown in Tables36 to 40.

TABLE 36 MMP-9 inhibition activities of compounds of the formula (I)Comp. IC₅₀ (μmol/1) No. 1st 2nd Average 2 45.1 24.7 34.9 8 36.7 30.133.4 9 42.2 43.9 43.1 10 42.6 54.2 48.4 11 31.9 33.7 32.8 12 32.9 24.528.7 13 20.1 16.1 18.1 14 47.4 42.2 44.8 15 46.8 52.7 49.8 16 49.8 43.946.8 17 43.8 28.8 36.3 18 18.3 26.6 22.5 19 10.1 13.2 11.7 20 24.1 32.028.1 21 11.7 18.1 14.9 22 17.9 17.4 17.7 23 42.5 54.8 48.7 24 28.9 34.931.9 25 21.9 30.0 26.0 26 31.9 31.5 31.7 27 26.6 24.5 25.6 28 23.3 24.624.0 29 30.8 24.5 27.7 30 11.3 17.5 14.4 32 26.7 24.0 25.4 33 30.6 31.931.8 34 30.2 26.9 28.6 35 14.6 22.1 18.4 36 19.7 24.3 22.0 37 4.5 7.05.8 38 13.7 19.1 16.4 39 16.1 29.2 22.7 40 13.5 28.7 21.1 41 15.1 13.714.4 42 41.4 40.7 41.4 43 24.7 20.2 22.5 44 19.6 26.8 23.2 45 33.8 26.330.1 46 36.2 34.8 35.5 48 20.6 18.2 19.4 49 15.6 18.0 16.8 50 25.7 23.024.3 51 27.3 32.1 29.7 52 21.6 30.2 25.9 53 22.6 29.3 26.0 54 26.2 30.328.3 55 25.3 30.0 27.7 56 39.9 33.5 36.7

TABLE 37 MMP-9 inhibition activities of compounds of the formula (I)Comp. IC₅₀ (μmol/ 1) No. 1st 2nd Average 57 38.7 3 5.1 36.6 60 48.5 45.447.0 61 39.7 42.2 40.9 67 56.9 43.1 50.0 70 42.1 57.1 49.6 71 42.9 37.440.2 72 40.8 41.5 41.2 73 44.6 47.9 46.3 74 49.6 49.4 49.5 76 34.0 33.833.9 77 41.4 35.2 38.3 78 44.1 36.0 40.1 79 39.0 36.6 37.8 82 52.9 19.036.0 83 66.2 14.2 36.0 84 43.4 14.2 28.8 85 52.8 41.1 47.0 86 41.8 41.541.7 87 20.5 25.3 22.9 88 37.7 57.5 47.6 90 18.7 37.4 28.0 91 20.0 35.727.9 92 15.4 20.6 18.0 93 48.3 44.8 46.6 94 4.2 7.0 5.6 95 26.7 27.026.9 96 24.5 21.3 22.9 97 45.7 35.3 40.5 98 8.8 7.8 8.3 99 20.5 30.025.3 100 38.7 26.0 32.4 101 37.8 18.5 28.2 102 18.2 14.0 16.1 103 8.910.7 9.8 104 21.1 17.5 19.3 105 14.2 17.0 15.6 106 11.7 8.4 10.1 107 8.07.4 7.7 108 15.0 35.0 25.0 109 20.8 26.9 23.9 110 35.2 29.3 32.3 11145.5 26.8 36.2 112 38.2 30.9 34.6 115 31.8 26.5 29.2 117 30.0 39.3 34.7118 32.3 35.1 33.7 119 28.0 23.4 25.7

TABLE 38 MMP-9 inhibition activities of compounds of the formula (I)Comp. IC₅₀ (μmol/ 1) No. 1st 2nd Average 120 39.8 39.4 39.6 122 12.616.3 14.5 123 13.9 12.4 13.2 124 16.1 18.6 17.4 125 10.1 15.8 13.0 12629.4 21.8 25.6 127 1.4 2.8 2.1 128 19.2 10.3 13.0 129 11.8 6.7 9.3 1307.7 8.4 8.1 131 2.0 3.0 2.5 132 1.2 2.4 1.8 135 28.2 20.4 24.3 136 21.329.2 25.3 137 17.7 37.1 27.4 138 22.3 15.7 19.0 140 22.3 21.9 22.6 14119.9 18.1 19.0 142 20.4 22.4 21.4 144 4.8 14.9 9.9 145 1.7 4.1 2.9 14618.4 29.4 23.9 147 35.0 39.9 37.5 148 33.5 21.7 27.6 150 14.8 11.4 13.1152 29.6 16.3 23.0 153 35.8 16.9 26.4 155 24.3 43.5 33.9 156 38.3 41.840.1 157 7.4 5.5 6.5 159 7.9 — 7.9 160 9.4 — 9.4 161 6.0 — 6.0 162 6.3 —6.3 163 9.2 — 9.2 164 5.4 5.9 5.7 165 3.2 — 3.2 166 7.8 — 7.8 167 14.0 —14.0 168 7.1 7.3 7.2 169 6.0 9.6 7.8 170 5.6 — 5.6 172 0.82 1.1 0.96 1749.0 — 9.0 177 10.7 6.1 8.4 178 11.8 12.5 12.2 179 8.3 — 8.3 181 11.6 —11.6

TABLE 39 MMP-9 inhibition activities of compounds of the formula (I)Comp. IC₅₀ (μmol/1) No. 1st 2nd Average 182 7.0 5.6 6.4 184 20.0 10.615.3 186 12.3 — 12.3 188 6.2 — 6.2 189 11.1 — 11.1 191 7.4 4.4 5.9 1928.1 13.6 10.9 193 10.5 — 10.5 194 4.9 8.4 6.7 195 11.6 — 11.6 196 11.2 —11.2 197 10.3 10.9 10.6 199 5.7 6.2 6.0 202 6.3 — 6.3

TABLE 40 MMP-9 inhibition activities of compounds of the formula (IV)Int. IC₅₀ (μmol/1) No. 1st 2nd Average 1 28.6 42.9 35.6 2 31.4 59.9 45.73 21.3 37.3 29.3 5 26.9 — 26.9 6 33.0 — 33.0 7 38.0 — 38.0 10 26.9 46.636.8 11 17.6 15.9 16.8 12 25.3 24.5 24.9 16 24.5 18.9 21.7 19 29.9 35.632.8 20 38.9 49.6 44.3 21 31.6 54.4 43.0 24 43.1 31.8 37.4 25 58.9 35.337.1 47 24.4 26.5 25.5 49 29.5 29.0 29.3 50 33.9 25.3 29.6 51 31.6 26.028.8 52 61.5 50.4 56.0 54 38.7 33.9 36.3 55 32.5 25.5 29.0 57 49.4 37.543.5 59 11.4 — 11.4 61 8.2 — 8.2 62 4.5 — 4.5 63 4.3 — 4.3 64 4.4 — 4.4

Test Example 4 Measurement of the Inhibitory Action AgainstCapillary-like Tube Formation of Vascular Endothelical Cells

(1) Test Method

Three Dimensional Culture of Vascular Endothelical Cells EmployingCollagen Gel

With reference to the method disclosed in a literature (Hayashi, J. N.et al, Virchows arch. (B), Vol. 60,245-252, 1991, Lee, D. Y. et al, LifeScience, Vol. 60, 127-134, 1997), evaluation was carried out by thefollowing method.

1) Preparation of Underlayer Collagen Gel

7 Parts by volume of type I-a collagen (manufactured by Nitta GelatinK.K.) and 2 parts by volume of Dulbecco's Modified Eagle Medium(concentration: 5 times, containing no NaHCO₃; No. D-5648, manufacturedby Sigma Co.) were thoroughly mixed under cooling with ice, and then onepart by volume of a collagen gel-reconstructing buffer solution (2.2%NaHCO₃/0.2M HEPES/0.05N NaOH) was added thereto. To withdraw bubbles,centrifugal separation and supersonic treatment were carried out, andthen 400 μl of the gel was introduced into 24 well multi-well plate(Code 3047, manufactured by Falcon Co.) and incubated at 37° C. forabout 10 minutes for gelation.

2) Three Dimensional Culture of CPAE Cells

On the gelled collagen, CPAE cells (bovine pulmonary-derived vascularendothelical cells; ATCC CCL209, purchased from Dainippon Seiyaku K.K.)was inoculated in a concentration of 4×10⁴ cells/400 μl/well (Day 0).Thereafter, the cells were cultured overnight at 37° C. in a 5% CO₂incubator. Next day (Day 1), after confirming that the cells werenormally proliferating, the culture solution was removed by aspiration,and a fresh collagen gel (prepared in the same manner as the abovelayer) was overlaid in an amount of 200 μl/well and gelled.

3) Evaluation of the Effect of the Test Materials

On the gel, the test materials dissolved in 10% fetal bovineserum-containing Dulbecco's Modified Eagle Medium (No. D-5648,manufactured by Sigma Co.) (prepared to have a concentration four timesthe final concentration) was added in an amount of 200 pl, and culturingwas continued under the same conditions. Upon expiration of three daysfrom stratification (Day 4), capillary-like tube formation was observedby a microscope, and an optional field of view was photographed with 100magnifications, whereupon the number of capillary-like structures formed(the number of networks) were visually counted with reference to themethod disclosed in a literature by Yeong, H. et al (Cancer Research,Vol. 56, 2428-2433, 1996). For each test sample, 2 well treatment wascarried out, and a total of five fields of view were photographed forevaluation.

(2) Test Results

TABLE 41 Inhibition ratio against capillary-like tube formation of CPAEbovine vascular endothelical cells (n = 5) Treating Solventconcentration control Compound No. 107 Compound No. 164 (μM) 0 0.1 1 10100 0.1 1 10 100 Number of 30.8 ± 2.2 20.0 ± 5.7 18.2 ± 1.6 11.8 ± 5.0 2.0 ± 2.8 23.6 ± 3.2 17.2 ± 4.1 17.2 ± 6.0 10.4 ± 5.7 networks Average± SD Inhibition — 35* 41* 62* 93* 23 44* 44* 66* ratio (%) p < 0.01against vehicle control group (Dunnett multiple comparison test)

Test Example 5 Measurement of the Inhibition Effects of Compound No. 107and Compound No. 164 Against Tumor Growth of Meth A/AD

(1) Preparation of Meth A/AD Strain

Meth A mouse fibrosarcoma cells intraperitoneally subcultured in mouse(supplied from Sasaki Institute) were cultured at 39° C. for 10 days in5% CO₂ (using 10% fetal bovine serum-containing RPMI culture medium(manufactured by Flow Laboratories)) and then inoculated subcutaneouslyto BALB/c mouse. The tumor grown for 30 days, was taken out and passedthrough a metal mesh to obtain single cells, which were again returnedand continuously cultured in vitro (37° C.). When subculture wasrepeated for about 1 month, Meth A/AD cell strain was obtained whichshowed adhesion to the culture dish and which constantly proliferated.The Meth A/AD strain showed substantially the same doubling time andcell proliferation as the parental cells in vitro, but the subcutaneousor growth rate in intradermal region in vivo was at a level of from ½ to⅓ of the parental cell. Further, the Meth A/AD strain showed noproliferation in the peritoneal cavity of mouse, which is observed inthe parental cells. On the other hand, the Meth A/AD strain alwaysproduces and secretes MMP-2 in the supernatant in in vitro culture, butwhen TNF-α (50 ng/ml) was added in the culture solution, it producedMMP-9 remarkably.

(2) Inhibition Effects Against in Vivo Tumor Growth of the Meth A/ADStrain

With reference to the method by Keneda et al (Cancer Research, Vol. 58,290-295, 1998), the inhibitory effect on tumor growth were evaluated.Namely, 1×10⁶ Meth A/AD cells cultured in vitro (suspended in 0.05 ml ofa Hanks equilibrium salt solution) were intradermaly transplanted to thedosal skin of a male BALB/c AnNCrj mouse of 5 weeks old (purchased fromCharles River Japan, Inc.) (Day 0). The test materials wasintraperitoneally administered (administered in a volume of 10 ml/kg)upon expiration of 2 hours from the cell implantation and once a day onDay 1 to 4 and Day 7 to 11 (total of 10 times). Compound No. 107 wassuspended in a 1% Tween 80 physiological sodium chloride aqueoussolution, and Compound No. 164 was dissolved in 100 mM Tris-HCl (pH8.5)/150 mM NaCl, for administration. To the vehicle control group, therespective solvents containing no test materials were administered inthe same manner. The measurement of the body weight and the observationof the general findings were carried out everyday up to Day 22 or 24,and the tumor diameters (the long diameter and the short diameter) weremeasured by a slide gauge every one day, and the difference in the tumorvolume between the vehicle control group and the drug-treated group wasevaluated. The tumor volume was calculated in accordance with thecalculation formula of [(long diameter)×(short diameter)²×½].

(3) Results

By the intraperitoneally administration in a total of 10 times ofCompound No. 107 (100 mg/kg) and Compound No. 164 (30 mg/kg), the tumorgrowth of Meth A/AD was significantly inhibited, and the inhibitionratios were 63.5% and 49.8%, respectively. During the test period, nodistinct toxicity or inhibition against the increase of the body weightderived from the drug administered group, was observed by theobservation of the general findings.

TABLE 42 Inhibition effects of Compound 107 against the tumor growth ofMeth A/AD (Intraperitoneal administration) Dose Tumor Tumor (mg/kgNumber of volume(Day 22) growth Administrated × test Average ± standardinhibition group 11 times) animals deviation (mm³) ratio (%) Vehiclecontrol — 6 1058 ± 556  — Compound No. 100 5 386 ± 275* 63.5* 107 *p <0.05 (t-test)

TABLE 43 Inhibition effects of Compound 107 against the tumor growth ofMeth A/AD (Intraperitoneal administration) Dose Tumor Tumor (mg/kgNumber volume(Day 24) growth Administrated × of test Average ± standardinhibition group 11 times) animals deviation (mm³) ratio (%) Vehiclecontrol — 21 2045 ± 987 — Compound No. 30 6 1027 ± 907* 49.8* 164 *p <0.05 (t-test)

Test Example 6 Measurement of the Inhibition Effects of Compound No. 37and Compound No. 157 Against Experimental Lung Metastatis of Colon 26/AD

(1) Preparation of Colon 26/AD Cell Strain

Colon 26 mouse colon cancer cells (obtained from Cancer ChemotherapyCenter Foundation for Cancer Research) were transplanted subcutaneouslyto BALB/c mouse, 10 days later, the grown tumor was taken out. It washashed in a Hanks equilibrium salt solution and passed through a metalmesh to obtain single cells, which were cultured in vitro (37° C., 5%CO₂) (using 10% fetal bovine serum-containing Dulbecco's Modified EagleMedium (D-5648, manufactured by Sigma Co.)). After subculture forseveral times, Colon 26/AD cell strain was obtained which showedadhesion to the culture dish and which proliferated constantly. The samecell strain always produced and secreted MMP-2 in the supernatant of thein vitro culture, but when cultured by an addition of TNF-α (50 ng/ml)in the culture solution, it produced MMP-9 remarkably.

(2) Inhibition Effects Against Experimental Lung Metastatis of Column26/AD

With reference to the method by Tsuruo et al (Japanese Journal of CancerResearch (Gann), Vol. 75, 193-198, 1984), the inhibition effects againstexperimental lung metastasis were evaluated. Namely, 3×10⁴ Colon 26/ADcells (suspended in 0.2 ml of Minimum Essential Medium (manufactured byNissui Seiyaku K.K.)) cultured in vitro were transplanted through thetail vein of a male BALB/c AnNCrj mouse (purchased from Charles RiverJapan, Inc.) of 6 weeks old (Day 0). In the case of Compound No. 37, itwas suspended in a 1% Tween 80/physiological sodium chloride aqueoussolution and intraperitoneally administered (administered in a volume of10 ml/kg) immediately (within 5 minutes) before transplantation of thecells, 2 hours later and once per day on Day 1-4 and Day 7-11 (a totalof 11 times). Further, in the case of Compound No. 157, it was dissolvedin 100 mM Tris-HCl (pH 8.5)/150 mM NaCl and forcibly orally administered(administered in a volume of 10 ml/kg) by means of a metal sonde 30minutes before transplantation of the cells, in the morning and eveningof Day 1 and once per day on Day 2-4, Day 7-11 and Day 14 (a total of 12times). To the vehicle control group, the respective solvents containingno test materials, were administered in the same manner. On Day 14 orDay 15, the lung of each mouse was taken out, and the weight wasmeasured, and the metastatis inhibition rate was calculated inaccordance with the following formula.${{Inhibition}\quad {ratio}\quad (\%)} = {1 - {\left( \frac{A - B}{C - B} \right) \times 100}}$

where

A is the weight of lung of the treated group

B is the average weight of lung of the normal group

C is the average weight of lung of the solvent control group.

(3) Results

Compound No. 37 (30 mg/kg) in the intraperitoneal administration in atotal of 11 times, and Compound No. 157 (10 mg/kg) in oraladministration in a total of 12 times, inhibited the experimentalmetastatis of Colon 26/AD to lung significantly, and their inhibitionratios were 40.2% and 59.5%, respectively. During the test period, nodistinct toxicity or inhibition against an increase of the body weightderived from the drug-administered group was observed from theobservation of general findings.

TABLE 44 Inhibition effects of Compound No. 37 against experimental lungmetastatis of Colon 26/AD Lung weight Admin- Dose Number Weight ofincrease (g) Metastatis istrated (mg/kg × of test lung (g) againstnormal inhibition group 11 times) animals (Day 14) mouse ratio (%)Normal — 9 0.213 ± 0.02 — — mouse Vehicle — 8 0.402 ± 0.07 0.189 ± 0.07— control Com- 30 5 0.326 ± 0.06  0.113 ± 0.06* 40.2%* pound No. 37 *p <0.05 (t-test)

TABLE 45 Inhibition effects of Compound No. 157 against experimentallung metastatis of Colon 26/AD Lung weight Admin- Dose Number Weight ofincrease (g) Metastatis istrated (mg/kg × of test lung (g) againstnormal inhibition group 11 times) animals (Day 15) mouse ratio (%)Normal — 12 0.181 ± 0.35 — — mouse Vehicle — 18 0.364 ± 0.11 0.183 ±0.11 — control Com- 10 6 0.257 ± 0.08  0.076 ± 0.08* 59.5%* pound No.157 *p < 0.05 (t-test)

Test Example 7 Inhibition Effects of Compound No. 164 Against MouseArthritis Model Induced by a Single Immunization with Collagen

(1) Preparation of Sensitized Antigen for Inducing Arthritis

With reference to the method by Kato, F. et al (Annals of the RheumaticDiseases, Vol. 55, 535-539, 1996), a bovine type II collagen (K-41,manufactured by collagen Gijutsu Kenkyukai) solution (3 mg/ml) dissolvedin 0.05N acetic acid and Freund's complete adjuvant (Freund, AdjuvantComplete; No. F5506, manufactured by Sigma Co.) were mixed in equalamounts and subjected to ultrasonic treatment (under cooling with ice,20 seconds×3 times) to obtain a uniform emulsion.

(2) Antigen Sensitization of Mouse and Drug Administration

0.1 ml (150 μg) of the antigen prepared as described above, wasadministered to the tail head skin of a female DBA/1JNCrj mouse of 5weeks old (purchased from Charles River Japan, Inc.) (Day 0). After 2weeks from sensitization (Day 14), Compound No. 164 (50 mg/kg) suspendedin a 1% Tween 80/physiological sodium chloride aqueous solution wasintraperitoneally administered (administered in a volume of 10 ml/kg)once a day continuously for 5 weeks. To the vehicle control group, the1% Tween 80/physiological sodium chloride aqueous solution wasadministered in the same manner.

(3) Medicinal Effect

Sideration of arthritis was observed once a week from Day 1 inaccordance with the following evaluation standards disclosed in aliterature of Kato, F. et al (Annals of the Rheumatic Diseases, Vol. 55,535-539, 1996) with respect to Knuckle joints of the respective fourlimbs. When swelling was observed with respect to at least one limbamong four limbs, such was judged to be sideration.

(4) Results

By the intraperitoneal administration of 50 mg/kg of Compound No. 164everyday, sideration of arthritis was significantly delayed as comparedwith the control group (p<0.01; Wilcoxon ranking test). During the testperiod, no distinct toxicity or inhibition against the body weightincrease derived from the drug-administered group was observed byobservation of general findings.

TABLE 46 Influence of Compound No. 164 against mouse arthritis modelinduced by a single immunization with collagen (intraperitonealadministration) Adminis- Dose Number Sideration ratio of arthritis(number of diseased tration (mg/ of test animals/number of testedanimals) group kg) animals Day 14* Day 21 Day 28 Day 35 Day 42 Day 49Vehicle — 8 0/8 2/8 7/8 8/8 8/8 8/8 control Compound 40 8 0/8 0/8 2/86/8 7/8 7/8 No. 164 *At the initial of administration of drug

What is claimed is:
 1. A medical composition containing, as an activeconstituent, a nitroetheneamine derivative represented by the formula(I):

wherein R¹ is a hydrogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted or a cyano group; each ofR² and R³ which are independent of each other, is a hydrogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted, a heterocyclicgroup which may be substituted or a —A—R⁷ group (wherein A is S, SO,SO₂, SO₃, CO or CO₂, and R⁷ is a hydrogen atom, an alkyl group which maybe substituted, an alkenyl group which may be substituted, an alkynylgroup which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted); or R² and R³ may form, together with the N atom, a N═CR⁸R⁹group (wherein each of R⁸ and R⁹ which are independent of each other, isa hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted, a cyano group, a nitrogroup, an alkoxy group which may be substituted, an aryloxy group whichmay be substituted or a —A—R⁷ group (wherein A and R⁷ are as definedabove)); each of R⁴ and R⁵ which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted, an alkoxy group which maybe substituted, a —A—R⁷ group (wherein A and R⁷ are as defined above),an amino group which may be substituted, a cyano group, an ester group,a hydroxyl group or an aryloxy group which may be substituted; or R⁴ andR⁵ may form, together with the N atom, a N═CR⁸R⁹ group (wherein R⁸ andR⁹ are as defined above); R⁶ is a hydrogen atom, a nitro group, a cyanogroup, a —A—R⁷ group (wherein A and R⁷ are as defined above), an alkylgroup which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted, a heterocyclicgroup which may be substituted, an alkoxy group which may besubstituted, a halogen atom or an amino group which may be substituted;and further at least two selected from R¹, R², R³, R⁴, and R⁵ maytogether, form a ring containing or not containing a hetero atom inaddition to the nitrogen atom; its stereoisomers, its tautomers or asalt thereof.
 2. A matrix metalloproteinase inhibitor containing, as anactive constituent, a nitroetheneamine derivative represented by theformula (I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1, itsstereoisomers, its tautomers or a salt thereof.
 3. The matrixmetalloproteinase inhibitor according to claim 2, characterized in thatit inhibits at least one matrix metalloproteinase selected from MMP-1,MMP-2, MMP-3, MMP-7 and MMP-9.
 4. The matrix metalloproteinase inhibitoraccording to claim 3, characterized in that it inhibits MMP-9.
 5. Anangiogenesis inhibitor containing, as an active constituent, anitroetheneamine derivative represented by the formula (I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1, itsstereoisomers, its tautomers or a salt thereof.
 6. An anticancer drugcontaining, as an active constituent, a nitroetheneamine derivativerepresented by the formula (I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1, itsstereoisomers, its tautomers or a salt thereof.
 7. A tumor cellinfiltration inhibitor containing, as an active constituent, anitroetheneamine derivative represented by the formula (I):

wherein R¹, R², R³, R⁴ R⁵ and R⁶ are as defined in claim 1, itsstereoisomers, its tautomers or a salt thereof.
 8. A tumor cellmetastatis inhibitor containing, as an active constituent, anitroetheneamine derivative represented by the formula (I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1, itsstereoisomers, its tautomers or a salt thereof.
 9. A therapeutic orpreventive agent for rheumatoid arthritis containing, as an activeconstituent, a nitroetheneamine derivative represented by the formula(I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1, itsstereoisomers, its tautomers or a salt thereof.
 10. A nitroetheneaminederivative represented by the formula (I-1):

wherein R^(1′) is a hydrogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted or a cyano group; each ofR^(2′) and R^(3′) which are independent of each other, is a hydrogenatom, an alkyl group which may be substituted (provided that aheterocyclic methyl group which may be substituted, is excluded), acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, a heterocyclic group which may be substituted or a—A′—R^(7′) group (wherein A′ is S, SO, SO₂, SO₃, CO or CO₂, and R^(7′)is a hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted); or R^(2′) and R^(3′)may form, together with the N atom, a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted); R^(4′) is an alkyl groupwhich may be substituted, an alkoxyphenyl group, a haloalkyloxyphenylgroup, a cycloalkyl group which may be substituted, a cycloalkenyl groupwhich may be substituted, an alkoxy group which may be substituted, a—A′—R^(7′) group (wherein A′ and R^(7′) are as defined above) or anamino group which may be substituted; R^(5′) is a hydrogen atom, analkyl group, an alkoxyphenyl group, a haloalkyloxyphenyl group, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an alkoxy group which may be substituted, a—A′—R^(7′) group (wherein A′ and R^(7′) are as defined above) or anamino group which may be substituted; R^(6′) is a hydrogen atom, a nitrogroup, a cyano group or a —A′—R^(7′) group (wherein A′ and R^(7′) are asdefined above) or an alkyl group which may be substituted; or R^(4′) andR^(5′) may form, together with the N atom, a N═CR^(8″)R^(9″) group(wherein R^(8″) and R^(9″) are as defined above); and further at leasttwo selected from R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) may togetherform a ring containing or not containing a hetero atom in addition tothe nitrogen atom; provided that (1) a case where R^(1′) or R^(4′) is analkyl group substituted by a hetero-ring which may be substituted, (2) acase where R^(1′), R^(3′), R^(5′) and R^(6′) are all hydrogen atoms,R^(2′) is a hydrogen atom, an alkyl group which may be substituted or anaryl group which may be substituted, and R^(4′) is

(wherein j is an integer of from 1 to 6), and (3) a case wherein R^(1′)is a hydrogen atom; each of R^(2′) and R^(3′) which are independent ofeach other, is a hydrogen atom, an alkyl group which may be substitutedor a phenyl group which may be substituted; R^(4′) is an alkyl which maybe substituted, a phenyl group which may be substituted, a —A′—R^(7′)group (wherein A′ and R^(7′) are as defined above) or an amino groupwhich may be substituted; R^(5′) is a hydrogen atom, an alkyl groupwhich may be substituted or a phenyl group which may be substituted; andR^(6′) is a hydrogen atom, are excluded; its stereoisomers, itstautomers or a salt thereof.
 11. The nitroetheneamine derivativeaccording to claim 10, wherein R^(1′) is a hydrogen atom; R^(2′) is ahydrogen atom, a heterocyclic group which may be substituted or a—A″—R^(7″) group (wherein A″ is CO, CO₂ or SO₂, and R^(7″) is an alkylgroup which may be substituted or an aryl group which may besubstituted); R^(3′) is a hydrogen atom, an alkyl group which may besubstituted (provided that a heterocyclic methyl group which may besubstituted, is excluded), a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ and R^(7″) are as defined above); orR^(2′) and R^(3′) may together form, a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted); R^(4′) is an alkyl groupwhich may be substituted (provided that a heterocyclic alkyl group whichmay be substituted, is excluded), an alkoxyphenyl group, ahaloalkyloxyphenyl group, a cycloalkyl group which may be substituted,an alkylsulfonyl group which may be substituted, an alkenylsulfonylgroup which may be substituted, an alkynylsulfonyl group which may besubstituted, a cycloalkylsufonyl group which may be substituted, acycloalkenylsulfonyl group which may be substituted, an arylsulfonylgroup which may be substituted, a sulfonyl group substituted by a heteroring which may be substituted or an amino group which may besubstituted; R^(5′) is a hydrogen atom; R^(6′) is a hydrogen atom or analkyl group; and further R^(2′) and R^(3′) may together form a ringcontaining or not containing a hetero atom in addition to the nitrogenatom; provided that (1) a case where R^(1′), R^(2′), R^(5′), and R^(6′)are hydrogen atoms; R^(3′) is a hydrogen atom or an alkyl group whichmay be substituted; and R^(4′) is an alkyl group which may besubstituted, an alkoxyphenyl group which may be substituted, ahaloalkyloxyphenyl group which may be substituted, an alkylsulfonylgroup which may be substituted, an alkenylsulfonyl group which may besubstituted, an alkynylsulfonyl group which may be substituted, acycloalkylsufonyl group which may be substituted, a cycloalkenylsulfonylgroup which may be substituted, an arylsulfonyl group which may besubstituted or a sulfonyl group substituted by a hetero ring which maybe substituted, and (2) a case where R^(1′), R^(3′), R^(5′) and R^(6′)are hydrogen atoms, R^(2′) is a heterocyclic group (provided that aheterocyclic group substituted by at least one halogen atom, isexcluded), and R^(4′) is an alkyl group which may be substituted, areexcluded; its stereoisomers, its tautomers or a salt thereof.
 12. Thenitroetheneamine derivative according to claim 11, wherein R^(1′) is ahydrogen atom; R^(2′) is a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ is CO, CO₂ or SO₂, and R^(7″) is analkyl group which may be substituted or an aryl group which may besubstituted); R^(3′) is a hydrogen atom, an alkyl group which may besubstituted (provided that a heterocyclic methyl group which may besubstituted, is excluded), a heterocyclic group which may be substitutedor a —A″—R^(7″) group (wherein A″ and R^(7″) are as defined above); orR^(2′) and R^(3′) may together form a N═CR^(8″)R^(9″) group (whereineach of R^(8″) and R^(9″) which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an aryl groupwhich may be substituted, a heterocyclic group which may be substitutedor an alkoxy group which may be substituted) or form a ring containingor not containing a hetero atom; R^(4′) is an alkylsulfonyl group whichmay be substituted, an alkenylsulfonyl group which may be substituted,an alkynylsulfonyl group which may be substituted, a cycloalkylsufonylgroup which may be substituted, a cycloalkenylsulfonyl group which maybe substituted, an arylsulfonyl group which may be substituted, asulfonyl group substituted by a hetero ring which may be substituted oran amino group which may be substituted; R^(5′) is a hydrogen atom; andR^(6′) is a hydrogen atom or an alkyl group; its stereoisomers, itstautomers or a salt thereof.
 13. The nitroetheneamine derivativeaccording to claim 12, wherein R^(1′) is a hydrogen atom; R^(2′) is aheterocyclic group which may be substituted or a —A″—R^(7″) group(wherein A″ is CO, CO₂ or SO₂, and R^(7″) is an alkyl group which may besubstituted or an aryl group which may be substituted); R^(3′) is ahydrogen atom, an alkyl group which may be substituted (provided that aheterocyclic methyl group which may be substituted, is excluded), aheterocyclic group which may be substituted or a —A″—R^(7″) group(wherein A″ and R^(7″) are as defined above); or R^(2′) and R^(3′) maytogether form a N═CR^(8″)R^(9″) group (wherein each of R^(8″) and R^(9″)which are independent of each other, is a hydrogen atom, an alkyl groupwhich may be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted or an alkoxy group which maybe substituted); R^(4′) is an alkylsulfonyl group which may besubstituted, an alkenylsulfonyl group which may be substituted, analkynylsulfonyl group which may be substituted, a cycloalkylsufonylgroup which may be substituted, a cycloalkenylsulfonyl group which maybe substituted, an arylsulfonyl group which may be substituted, asulfonyl group substituted by a hetero ring which may be substituted oran amino group which may be substituted; R^(5′) is a hydrogen atom; andR^(6′) is a hydrogen atom or an alkyl group; its stereoisomers, itstautomers or a salt thereof.
 14. The nitroetheneamine derivativeaccording to claim 11, wherein R^(1′) is a hydrogen atom; R^(2′) andR^(3′) together form a ring containing or not containing a hetero atomin addition to the nitrogen atom; R^(4′) is an alkyl group which may besubstituted, an alkoxyphenyl group, a haloalkyloxyphenyl group, acycloalkyl group which may be substituted, an alkylsulfonyl group whichmay be substituted, an alkenylsulfonyl group which may be substituted,an alkynylsulfonyl group which may be substituted, a cycloalkylsufonylgroup which may be substituted, a cycloalkenylsulfonyl group which maybe substituted, an arylsulfonyl group which may be substituted or asulfonyl group substituted by a hetero ring which may be substituted;R^(5′) is a hydrogen atom; and R^(6′) is a hydrogen atom or an alkylgroup; its stereoisomers, its tautomers or a salt thereof.